CN109761778A - A kind of method of synthesizing optical active alpha-hydroxypropanamide derivative - Google Patents
A kind of method of synthesizing optical active alpha-hydroxypropanamide derivative Download PDFInfo
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Abstract
The invention discloses a kind of methods of synthesizing optical active alpha-hydroxypropanamide derivative, belong to organic synthesis field.By using proline as chiral auxiliary; nucleophilic substitution occurs through acylation, bromination, de- chiral auxiliary and 4- cyano -3- 5-trifluoromethylaniline with methacrylic chloride, obtains the bromo- 2- hydroxy-2-methyl-N- of 3- [(4- cyano -3- trifluoromethyl) phenyl] propionamide.Nucleophilic substitution occurs with 4-hydroxybenzonitrile again, optically active compound 3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide is made.Ammonolysis occurs using the bromo- 2- hydroxy-2-methyl propionic acid of optically active 3- and 4- nitro-3-trifluoromethylaniline, nucleophilic substitution occurs with to acetaminophenol, optically active compound 3- (4- acetoxyl group phenoxy group)-N- [4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide is made.The present invention is a kind of to efficiently synthesize optical activity alpha-hydroxypropanamide derivative method.
Description
Technical field
The present invention relates to a kind of methods of synthesizing optical active alpha-hydroxypropanamide derivative, belong to organic synthesis field.
Background technique
(2S) -3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide
(Enobosarm, S-V) is a kind of selective non-steroidal androgen receptor regulator by the research and development of GTx company, the U.S., is used for
The diseases such as muscular atrophy and osteoporosis are treated, are currently carried out for amyotrophic clinical examination caused by kinds cancer
It tests.In completed 8 I phases and II clinical trial phase the results show that Enobosarm can be obviously improved the thin body of cancer patient
Weight and muscle strength and function.In the amyotrophic III phase clinic examination for the treatment of Patients with Non-small-cell Lung that in July, 2011 starts
Test, investigated Enobosarm whether be able to ascend patient body function and maintenance or increase Lean mass, data is
In arrangement, if Enobosarm can reach expected test objective, it will become first and be used to prevent and treat muscle loss
Or the drug of atrophy.
(2S) -3- (4- acetylamino phenoxy group)-N- [4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionyl
Amine (Andarine, S- VII) is equally a kind of selective androgen receptor regulator by the research and development of GTx company, the U.S., is used for
Treat the diseases such as muscular atrophy, osteoporosis and benign prostatauxe.The structure of Andarine and Enobosarm extremely phase
Seemingly, to its synthetic method research can thus class formation new drug exploitation provide technical support.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative,
The present invention is that operation is easy and efficient for one kind, the Lactoyl amine derivative synthetic method of high quality.
The technical solution used in the present invention is: a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative:
By nucleophilic substitution occurring with methacrylic chloride, obtains 1- (2- methyl 1. using proline as chiral auxiliary
Acryloyl group) nafoxidine -2- carboxylic acid；2. 1- (2- methylacryloyl) nafoxidine -2- carboxylic acid and N- bromo succinyl are sub-
Bromination reaction occurs for amine (NBS), obtains bromomethyl -3- methyl nafoxidine simultaneously [2,1-c] [Isosorbide-5-Nitrae] oxazines-Isosorbide-5-Nitrae-diketone；3. passing through
Hydrobromic acid hydrolysis, sloughs chiral auxiliary, obtains the bromo- 2- hydroxy-2-methyl propionic acid of optically active 3-.
Optically active bromo- 2- hydroxy-2-methyl propionic acid of 3- and thionyl chloride effect generate acyl chlorides, then with 4- cyano-
Nucleophilic substitution occurs for 3- 5-trifluoromethylaniline, obtains the bromo- 2- hydroxy-2-methyl-N- of 3- [(4- cyano -3- trifluoromethyl) benzene
Base] propionamide；The bromo- 2- hydroxy-2-methyl-N- of 3- [(4- cyano -3- trifluoromethyl) phenyl] propionamide under potassium carbonate catalysis
Nucleophilic substitution occurs with 4-hydroxybenzonitrile, optically active compound 3- (4- cyano-benzene oxygen)-N- [4- cyano -3- is made
Trifluoromethyl] -2- hydroxy-2-methyl propionamide.
Optically active bromo- 2- hydroxy-2-methyl propionic acid of 3- and thionyl chloride effect generate acyl chlorides, then with 4- nitro-
Nucleophilic substitution occurs for 3- 5-trifluoromethylaniline, obtains the bromo- 2- hydroxy-2-methyl-N- of 3- [(4- nitro -3- trifluoromethyl) benzene
Base] propionamide；The bromo- 2- hydroxy-2-methyl-N- of 3- [(4- nitro -3- trifluoromethyl) benzene under the catalysis of benzyl tributyl ammonium chloride
Base] propionamide with to acetaminophenol occur nucleophilic substitution, be made optically active compound 3- (4- acetyloxy phenyl oxygen
Base)-N- [4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide.The present invention is that one kind efficiently synthesizes optics work
The method of property Lactoyl amine derivative.Synthetic route is as follows:
(2S) -3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide
The synthesis of (Enobosarm, S-V)
(2R) -3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide
(R-V) synthesis
(2S) -3- (4- acetylamino phenoxy group)-N- [4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionyl
The synthesis of amine (Andarine, S- VII)
(2R) -3- (4- acetylamino phenoxy group)-N- [4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionyl
The synthesis of amine (R- VII)
Specific embodiment
Embodiment
The synthesis of (2R) -1- (2- methylacryloyl) nafoxidine -2- carboxylic acid (R- I)
D-PROLINE (20.80g, 180.8mmol) is dissolved in 2mol/L sodium hydroxide solution (90mL), acetone is added
(90mL), ice bath are cooled to 5~10 DEG C, under stirring, and methacrylic chloride (28.20g, 271.1mmol) and tetrahydrofuran is added dropwise
The mixed solution of (30mL), while pH11~12 of 2mol/L sodium hydroxide solution (113mL) control reaction solution are added dropwise.It drips
Finish, 3h is stirred at room temperature.Remove organic solvent under reduced pressure, Liquid Residue is adjusted to pH 5 with 6mol/L sulfuric acid solution, is extracted with ethyl acetate.
Liquid Residue continues to be acidified to pH 2 with 6mol/L sulfuric acid solution, is extracted with ethyl acetate (40mL × 5), merges organic layer, with nothing
Aqueous sodium persulfate dries, filters, and is concentrated under reduced pressure, obtains I 27.74g of white solid R-, yield 83.8%, mp.102~103 DEG C.(3R,
The synthesis of 8R)-bromomethyl -3- methyl nafoxidine simultaneously [2,1-c] [1,4] oxazines -1,4- diketone (II a)
Compound R-I (27.70g, 151.2mmol) is dissolved in N, in N- methylacetamide (120mL).Nitrogen protection condition
Under, the mixing that N- bromo-succinimide (NBS) (53.82g, 302.4mmol) and N, N- methylacetamide (200mL) is added dropwise is molten
Liquid.It is added dropwise, 5h is stirred at room temperature, reaction solution is poured into distilled water (600mL), solid is precipitated, and stirs 0.5h, filters, obtains
II a 24.16g of white solid, yield 60.9%, mp.151~153 DEG C are obtained with re-crystallizing in ethyl acetate to crude product.
(R)-(+) synthesis of the bromo- 2- hydroxy-2-methyl propionic acid (R- III) of -3-
Compound ii a (21.00g, 80.1mmol) is dissolved in 24% hydrobromic acid solution (168mL), reflux is warming up to, is protected
Temperature reaction 5h.End of reaction is cooled to room temperature, and is added distilled water (210mL), (40mL × 3) are extracted with ethyl acetate, are associated with
Machine layer extracts (40mL × 3) with saturated sodium bicarbonate solution, and combining water layer is acidified to pH 2 with concentrated hydrochloric acid, is extracted with ethyl acetate
It takes (30mL × 4), merges organic layer, anhydrous sodium sulfate dries, filters, and evaporating solvent under reduced pressure obtains crude product, is tied again with toluene
Crystalline substance filters, dry, obtains III 13.41g of white, needle-shaped crystals R-, yield 91.3%, mp.107~109 DEG C.
(R)-(-) the bromo- 2- hydroxy-2-methyl-N- of -3- [(4- cyano -3- trifluoromethyl) phenyl] propionamide (R- IV)
Synthesis
By compound R-III (6.00g, 32.9mmol), 4- cyano -3- 5-trifluoromethylaniline (6.79g, 36.5mmol) and
N, N- methylacetamide (42mL) are added in reaction flask, and ice bath is cooled to -15 DEG C, be added dropwise thionyl chloride (4.60g,
39.0mmol), -10 DEG C~-15 DEG C of reaction temperature are controlled.It is added dropwise, after insulated and stirred 0.5h, rises to 40 DEG C of reaction 3h.It will
Reaction solution is poured slowly into cold saturated sodium bicarbonate solution (120mL), is extracted with ethyl acetate (30mL × 3), is merged organic
Phase, saturated sodium chloride solution washing, filters, evaporating solvent under reduced pressure obtains crude product, with the mixing of petroleum ether and methyl tertiary butyl ether(MTBE)
Solution recrystallization, decolorizing with activated carbon obtain IV 9.30g of white solid R-, yield 80.4%, mp.133~135 DEG C.
(2S) -3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide
(S-V) synthesis
Compound R-IV (30.0g, 85mmol) and 4-hydroxybenzonitrile (12.2g, 102mmol) are dissolved in isopropanol
In (300mL), it is added Anhydrous potassium carbonate (35.4g, 256mmol), under the conditions of nitrogen protection, back flow reaction 0.5h.Evaporated under reduced pressure
Solvent, residue are dissolved in distilled water (300mL), are extracted with ethyl acetate (150mL × 2), merge organic phase, with 10% hydrogen-oxygen
Change sodium solution washing (100mL × 3), washed (200mL) with saturated sodium chloride solution, anhydrous sodium sulfate is dry, filters, filtrate rotation
It is dry, crude product is obtained, with re crystallization from toluene, active carbon decoloring obtains white solid S-V25.1g, yield 75.5%, mp.90~91 DEG C.
The synthesis of (2S) -1- (2- methylacryloyl) nafoxidine -2- carboxylic acid (S- I)
L-PROLINE (10.40g, 90.4mmol) is dissolved in 2mol/L sodium hydroxide solution (45mL), acetone is added
(45mL), ice bath is cooling, stirring.At 5~10 DEG C, methacrylic chloride (14.10g, 135.5mmol) and tetrahydrofuran is added dropwise
The mixed solution of (15mL), while 2mol/L sodium hydroxide solution (59mL) control reaction solution pH11~12 are added dropwise.It is added dropwise,
3h is stirred at room temperature, removes organic solvent under reduced pressure, Liquid Residue is acidified to pH 5 with 6mol/L sulfuric acid solution, is extracted with ethyl acetate.
Liquid Residue continues to be acidified to pH 2 with 6mol/L sulfuric acid solution, is extracted with ethyl acetate (20mL × 5), merges organic layer, with nothing
Aqueous sodium persulfate dries, filters, and is concentrated to dryness, and obtains I 13.18g of white solid S-, yield 79.6%, mp.101~103 DEG C.
The synthesis of (3S, 8S)-bromomethyl -3- methyl nafoxidine simultaneously [2,1-c] [1,4] oxazines -1,4- diketone (II b)
Compound S- I (13.00g, 71.0mmol) is dissolved in n,N-dimethylacetamide (56mL).Nitrogen protection condition
Under, the mixed solution of NBS (25.26g, 141.9mmol) and n,N-dimethylacetamide (95mL) is added dropwise.It is added dropwise, room temperature
5h is stirred, reaction solution is poured into distilled water (300mL), solid is precipitated, and stirs 0.5h, filters, obtains crude product, use ethyl acetate
Recrystallization, obtains II b 9.93g of white solid, yield 53.4%, mp.155~156 DEG C.
(S)-(+) synthesis of the bromo- 2- hydroxy-2-methyl propionic acid (S- III) of -3-
Compound ii b (9.90g, 37.8mmol) is dissolved in 24% hydrobromic acid solution (80mL), reflux is warming up to, is kept the temperature
React 5h.End of reaction is cooled to room temperature, and is added distilled water (100mL), is extracted with ethyl acetate (25mL × 3), is merged organic
Layer.Organic layer extracts (25mL × 3) with saturated sodium bicarbonate solution, combining water layer.Water layer enriching hydrochloric acid is acidified to pH 2, uses second
Acetoacetic ester extracts (20mL × 4), merges organic layer, adds anhydrous sodium sulfate dry, filters, filtrate is spin-dried for, obtains crude product, use toluene
Recrystallization, it is dry, obtain III 6.12g of white, needle-shaped crystals S-, yield 88.5%, mp.108~109 DEG C.
(S)-(-) the bromo- 2- hydroxy-2-methyl-N- of -3- [(4- cyano -3- trifluoromethyl) phenyl] propionamide (S- IV)
Synthesis
By compound S- III (30.0g, 164mmol), 4- cyano -3- 5-trifluoromethylaniline (33.9g, 182mmol) and N,
N- methylacetamide (210mL) is added in reaction flask, and ice bath is cooled to -15 DEG C, is added dropwise thionyl chloride (23.0g, 195mmol),
Reaction temperature is controlled at -10 DEG C~-15 DEG C.It finishes, insulated and stirred 0.5h, rises to 40 DEG C of reaction 2h.Reaction solution is poured slowly into
It in cold saturated sodium bicarbonate solution (60mL), is extracted with ethyl acetate (200mL × 3), merges organic phase, saturated sodium-chloride is molten
Liquid washing, anhydrous sodium sulfate are dried, filtered, are concentrated to dryness, and crude product are obtained, with the mixing of petroleum ether and methyl tertiary butyl ether(MTBE)
Solution recrystallization, decolorizing with activated carbon obtain IV 42.3g of white solid S-, yield 73.1%, mp.106~108 DEG C.
(2R) -3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide
(R-V) synthesis
Compound S- IV (30.0g, 85mmol) and 4-hydroxybenzonitrile (12.2g, 102mmol) are dissolved in isopropanol
In (300mL), it is added Anhydrous potassium carbonate (35.4g, 256mmol), under the conditions of nitrogen protection, back flow reaction 0.5h.Evaporated under reduced pressure
Solvent, residue are dissolved in distilled water (300mL), are extracted with ethyl acetate (150mL × 2), merge organic phase, with 10% hydrogen-oxygen
Change sodium solution washing (100mL × 3), wash (200mL) with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and depressurizes dense
It is reduced to dry, obtains crude product, with re crystallization from toluene, active carbon decoloring obtains white solid R-V23.2g, yield 69.7%, mp.91~92
℃。
(R)-(-) the bromo- 2- hydroxy-2-methyl-N- of -3- [(4- nitro -3- trifluoromethyl) phenyl] propionamide (R- VI)
Synthesis
By compound R-III (30.0g, 164mmol), 4- nitro-3-trifluoromethylaniline (26.0g, 126mmol) and N,
N- methylacetamide (200mL) is added in reaction flask, and ice bath is cooled to -15 DEG C, is added dropwise thionyl chloride (22.3g, 189mmol),
Temperature is controlled at -10 DEG C~-15 DEG C.It finishes, insulated and stirred 0.5h, rises to 40 DEG C of reaction 8h.Reaction solution is poured slowly into cold
It in saturated sodium bicarbonate solution (600mL), is extracted with ethyl acetate (150mL × 3), merges organic phase, saturated sodium chloride solution
Washing, anhydrous sodium sulfate are dried, filtered, are concentrated to dryness, be purified by silica gel column chromatography, and obtain VI 34.8g of yellow solid R-, are received
Rate 57.2%, mp.98~99 DEG C.
2.3.2 (2S) -3- (4- acetylamino phenoxy group)-N- [4- nitro -3- trifluoromethyl] -2- hydroxyl -2- first
The synthesis of base propionamide (S- VII)
Isopropanol is dissolved in by compound R-VI (20.0g, 54mmol) and to acetaminophenol (12.2g, 81mmol)
In (300mL), Anhydrous potassium carbonate (14.9g, 108mmol) and 10% benzyl tributyl ammonium chloride (2.0g), nitrogen protection is added
Under the conditions of, back flow reaction 4h.Evaporated under reduced pressure solvent, residue are dissolved in distilled water (200mL), and (100mL is extracted with ethyl acetate
× 2), merge organic phase, (1,0mL × 3) are washed with 10% sodium hydroxide solution, with anhydrous saturated sodium chloride solution (150mL)
Washing, anhydrous sodium sulfate are dried, filtered, are concentrated to dryness, and obtain crude product, and with re crystallization from toluene, it is solid to obtain yellow for active carbon decoloring
VII 18.5g of body S-, yield 77.8%, mp.70~72 DEG C.
(S)-(-) the bromo- 2- hydroxy-2-methyl-N- of -3- [(4- nitro -3- trifluoromethyl) phenyl] propionamide (S- VI)
Synthesis
By compound S- III (30.0g, 164mmol), 4- nitro-3-trifluoromethylaniline (26.0g, 126mmol) and N,
N- methylacetamide (200mL) is added in reaction flask, and ice bath is cooled to -15 DEG C, is added dropwise thionyl chloride (22.3g, 189mmol),
Temperature is controlled at -10 DEG C~-15 DEG C.It finishes, insulated and stirred 0.5h, rises to 40 DEG C of reaction 8h.Reaction solution is poured slowly into cold
It in saturated sodium bicarbonate solution (600mL), is extracted with ethyl acetate (150mL × 3), merges organic phase, saturated sodium chloride solution
Washing, anhydrous sodium sulfate dry, filter, and evaporating solvent under reduced pressure is purified by silica gel column chromatography, and obtain VI 34.6g of yellow solid S-, receive
Rate 56.9%, mp.100~102 DEG C.
(2R) -3- (4- acetylamino phenoxy group)-N- [(4- nitro -3- trifluoromethyl) phenyl] -2- hydroxy-2-methyl third
The synthesis of amide (R- VII)
Isopropanol is dissolved in by compound S- VI (10.0g, 27mmol) and to acetaminophenol (6.1g, 41mmol)
In (150mL), Anhydrous potassium carbonate (7.4g, 54mmol) and 10% benzyl tributyl ammonium chloride (1.0g), nitrogen protection item is added
Under part, back flow reaction 4h.Evaporated under reduced pressure solvent, residue are dissolved in distilled water (150mL), be extracted with ethyl acetate (100mL ×
2), merge organic phase, wash (100mL × 3) with 10% sodium hydroxide solution, wash (100mL), nothing with saturated sodium chloride solution
Aqueous sodium persulfate dries, filters, and is concentrated to dryness, and obtains crude product, and with re crystallization from toluene, active carbon decoloring obtains yellow solid R- VII
9.4g, yield 79.3%, mp.71~73 DEG C.
Claims (10)
1. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, which comprises the following steps:
(1) synthesis of the bromo- 2- hydroxy-2-methyl propionic acid of (R) -3- and the bromo- 2- hydroxy-2-methyl propionic acid of (S) -3-
1. under alkaline condition, nucleophilic substitution occurs for D-PROLINE and methacrylic chloride in organic solvent, (2R)-is obtained
1- (2- methylacryloyl) nafoxidine -2- carboxylic acid (R- I)；Parent occurs for L-PROLINE and methacrylic chloride under similarity condition
Core substitution reaction obtains (2S) -1- (2- methylacryloyl) nafoxidine -2- carboxylic acid (R- I).
Bromination reaction occurs for (2. 2R) -1- (2- methylacryloyl) nafoxidine -2- carboxylic acid and bromide reagent, obtain (3R,
8R)-bromomethyl -3- methyl nafoxidine simultaneously [2,1-c] [Isosorbide-5-Nitrae] oxazines-II a of Isosorbide-5-Nitrae-diketone；
Bromination reaction occurs for (2S) -1- (2- methylacryloyl) nafoxidine -2- carboxylic acid and bromide reagent, obtains (3S, 8S) -
Bromomethyl -3- methyl nafoxidine simultaneously [2,1-c] [Isosorbide-5-Nitrae] oxazines-II b of Isosorbide-5-Nitrae-diketone.
3. simultaneously [2,1-c] [Isosorbide-5-Nitrae] oxazines-Isosorbide-5-Nitrae-diketone through sour water solution, obtains (3R, 8R)-bromomethyl -3- methyl nafoxidine
(R) the bromo- 2- hydroxy-2-methyl propionic acid (R- III) of -3-；
Simultaneously [2,1-c] [Isosorbide-5-Nitrae] oxazines-Isosorbide-5-Nitrae-diketone obtains (S) -3- through sour water solution to (3S, 8S)-bromomethyl -3- methyl nafoxidine
Bromo- 2- hydroxy-2-methyl propionic acid (S- III).
4. the bromo- 2- hydroxy-2-methyl propionic acid of (R) -3- and chlorination reagent act on, then exist with 4- cyano -3- 5-trifluoromethylaniline
Nucleophilic substitution occurs under the conditions of alkalinity and certain temperature, obtains the bromo- 2- hydroxy-2-methyl-N- of (R) -3- [(4- cyano -3- three
Methyl fluoride) phenyl] propionamide；
(S) the bromo- 2- hydroxy-2-methyl propionic acid of -3- and chlorination reagent act on, then with 4- cyano -3- 5-trifluoromethylaniline in alkali
Nucleophilic substitution occurs under the conditions of property and certain temperature, obtains the bromo- 2- hydroxy-2-methyl-N- of (S) -3- [(4- cyano -3- trifluoro
Methyl) phenyl] propionamide.
(2) (2S) -3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide and
The synthesis of (2R) -3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide
Under base catalysis, in aprotic polar organic solvent, the bromo- 2- hydroxy-2-methyl-N- of (R) -3- [(4- cyano -3- trifluoro
Methyl) phenyl] nucleophilic substitution occurs for propionamide and 4-hydroxybenzonitrile, compound (2S) -3- (4- cyano-benzene oxygen)-is made
N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide (S-V)；
Under base catalysis, in aprotic polar organic solvent, the bromo- 2- hydroxy-2-methyl-N- of (S) -3- [(4- cyano -3- trifluoro
Methyl) phenyl] nucleophilic substitution occurs for propionamide and 4-hydroxybenzonitrile, compound (2R) -3- (4- cyano-benzene oxygen)-is made
N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide (R-V).
(3) (2S) -3- (4- acetoxyl group phenoxy group)-N- [4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionyl
Amine and (2S) -3- (4- acetoxyl group phenoxy group)-N- [4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide
Synthesis
1. the bromo- 2- hydroxy-2-methyl propionic acid of (R) -3- is reacted with chlorination reagent, then sent out with 4- nitro-3-trifluoromethylaniline
Raw nucleophilic substitution, obtains the bromo- 2- hydroxy-2-methyl-N- of (R) -3- [(4- nitro -3- trifluoromethyl) phenyl] propionamide (R-
Ⅵ)；
(S) the bromo- 2- hydroxy-2-methyl propionic acid of -3- is reacted with chlorination reagent, is then occurred with 4- nitro-3-trifluoromethylaniline
Nucleophilic substitution obtains the bromo- 2- hydroxy-2-methyl-N- of (S) -3- [(4- nitro -3- trifluoromethyl) phenyl] propionamide (S-
Ⅵ)。
2. under phase transfer catalyst effect, the bromo- 2- hydroxy-2-methyl-N- of (R) -3- [(4- nitro -3- trifluoromethyl) phenyl]
With to acetaminophenol nucleophilic substitution occurs for propionamide, and compound (2S) -3- (4- acetoxyl group phenoxy group)-N- is made
[4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide (S- VII)；
Under phase transfer catalyst effect, the bromo- 2- hydroxy-2-methyl-N- of (S) -3- [(4- nitro -3- trifluoromethyl) phenyl] third
With to acetaminophenol nucleophilic substitution occurs for amide, and compound (2R) -3- (4- acetoxyl group phenoxy group)-N- is made
[4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide (R- VII).
The present invention is a kind of to efficiently synthesize optical activity alpha-hydroxypropanamide derivative method.
2. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (1) exist according to claim 1
In the alkaline condition is sodium hydroxide, potassium hydroxide, ammonium hydroxide, one of lithium hydroxide.
3. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (1) exist according to claim 1
In organic solvent is one of ketone and tetrahydrofuran mixed solvent, such as acetone, butanone, 2 pentanone of low molecular weight.
4. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (1) exist according to claim 1
In bromide reagent is the carbon tetrachloride solution of N- bromo-succinimide (NBS) or bromine.
5. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (1) exist according to claim 1
In acid used is sulfuric acid, hydrochloric acid, hydrobromic acid, preferably 24% hydrobromic acid.
6. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (1) exist according to claim 1
In chlorination reagent used is thionyl chloride, phosphorus trichloride and phosphorus pentachloride, preferably thionyl chloride.
7. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (1) exist according to claim 1
In alkali used is sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, N-methylcyclohexylamine, preferably triethylamine.Reaction temperature
Degree is preferably room temperature.
8. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (2) exist according to claim 1
In alkali used is sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, N-methylcyclohexylamine, preferably potassium carbonate.
9. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (2) exist according to claim 1
In aprotic polar organic solvent used is n,N-Dimethylformamide or n,N-dimethylacetamide.
10. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (3) according to claim 1
It is, phase transfer catalyst is benzyl tributyl ammonium chloride, benzyl tributyl ammonium bromide, benzyltriethylammoinium chloride, benzyl three
Ethyl phosphonium bromide ammonium etc..It is preferred that benzyl tributyl ammonium chloride.
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| CN110981794A (en) * | 2019-12-19 | 2020-04-10 | 宁波耆健医药科技有限公司 | Synthetic method of nicotinate |
| CN111018740A (en) * | 2019-12-20 | 2020-04-17 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester |
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| CN111646922A (en) * | 2020-07-21 | 2020-09-11 | 阿里生物新材料（常州）有限公司 | Synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid |
| CN112250599A (en) * | 2020-11-24 | 2021-01-22 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester |
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| CN111646922B (en) * | 2020-07-21 | 2022-03-11 | 阿里生物新材料（常州）有限公司 | Synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid |
| CN112250599A (en) * | 2020-11-24 | 2021-01-22 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester |
| CN112250599B (en) * | 2020-11-24 | 2022-03-11 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester |
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