CN101555211A - Chemical synthesis method of 2-acylamino-3-biphenyl propionic acid - Google Patents
Chemical synthesis method of 2-acylamino-3-biphenyl propionic acid Download PDFInfo
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Abstract
The invention relates to a chemical synthesis method of a 2-acylamino-3-biphenyl propionic acid, and the reaction equation is shown on the right, wherein X is chlorine, bromine, iodine, methylsulfonyl or tosyl; R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or benzyl; HY is hydrochloric acid, formic acid, acetic acid, citric acid, oxalic acid, tartaric acid, sulfuric acid, nitric acid or phosphoric acid; R2 is methyl, ethyl, propyl, isopropyl, benzyl or 4-chlorobenzyl. Preferably, the R1 prefers to ethyl or isobutyl; HY prefers to hydrochloric acid; and R2 prefers to ethyl. The invention has short route, simple operation, high reagent selectivity, low production cost, high production purity and high yield, is suitable for large-scale industrial production, and has larger economic and social benefits.
Description
Technical field
The present invention relates to the synthetic field of compound, more specifically, relate to the field of chemical synthesis of a kind of biphenylalanine derivative, be meant the chemical synthesis process of 2-acyl amino-3-biphenyl propionic acid especially.
Background technology
2-acyl amino-3-biphenyl propionic acid, English name: 2-acylamino-3-biphenyl-propanoic acid, structural formula is suc as formula shown in (I):
It is a kind of chemical intermediate, has purposes very widely at chemical industry and the synthetic field of medicine, product after it splits is the key intermediate of more synthetic new drugs, be mainly used to synthetic polypeptide or amino acids or medicine, as the phenyllacetyl chloride resin, three p-methoxyphenyl chloracetyl resins, antitumor drug Sostatin etc.
The building-up process of 2-acyl amino-3-biphenyl propionic acid is at document: Analogs of luteinizing hormone-releasinghormone with modification in position (progestin releasing factor analogs and correction position, Yabe, people such as Yuichiro, Chemical ﹠amp; Pharmaceutical Bulletin, (1976), 24 (12), report is arranged in 3149-57), concrete synthetic route is as follows:
The shortcoming that this route exists is: because reagent selectivity is not high, make reaction scheme longer, promptly acyl group need be sloughed earlier in the 3rd step, added in the 4th step again; Used material and reagent are more, operate comparatively loaded down with trivial detailsly, and cost is higher, yield lower (64%), and economy and practicality are not high.
Summary of the invention
Main purpose of the present invention is exactly the problems and shortcomings at above existence; a kind of chemical synthesis process of brand-new 2-acyl amino-3-biphenyl propionic acid is provided; this method route is short; easy and simple to handle, the reagent selectivity height, production cost is low; the product purity height; the yield height is fit to large-scale industrial production, has bigger economic benefit and social benefit.
To achieve these goals, the technical scheme of this aspect employing is as follows:
The chemical synthesis process of this 2-acyl amino-3-biphenyl propionic acid is characterized in that, comprises the steps:
Wherein, X can be chlorine, bromine, iodine, methylsulfonyl or p-toluenesulfonyl.
R1 can be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl or phenmethyl; Preferred ethyl or isobutyl-.
HY is acidic substance, can be hydrochloric acid, formic acid, acetate, citric acid, oxalic acid, tartrate, sulfuric acid, nitric acid or phosphoric acid; Preferred hydrochloric acid.
R2 can be methyl, ethyl, propyl group, sec.-propyl, phenmethyl or to chlorophenylmethyl; Preferred ethyl.
Preferably, in step a, after adding reaction raw materials (compound shown in compound shown in the formula IV and the formula V), add basic solution and can promote the carrying out that react as catalyzer, obtain formula VII intermediate compound (as shown below), carry out titration with described HY acidic solution again, obtain compound shown in the formula III.Concrete reaction formula is as shown below:
Wherein, described formula VII intermediate compound does not extract separately, is directly used in following reaction.
Preferably, in step a, described basic solution can be sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood or diazabicylo (DBU) solution.
Preferably, in step a, described alkali: mole proportioning that feeds intake of compound shown in the described formula IV is (1.0～3.0): 1.0.
Preferably, in step a, described HY acidic substance: mole proportioning that feeds intake of compound shown in the described formula IV is (1.0～5.0): 1.0.
Preferably, in step a, compound shown in the described formula V: mole proportioning that feeds intake of compound shown in the described formula IV is (1.0～2.0): 1.0.
Preferably, in step a, temperature of reaction is-5～50 ℃.
More preferably, in step a, compound shown in compound shown in the described formula IV and the described formula V makes compound shown in the described formula III after reacting in solvent (solvent 1).
Preferably, in step a, described solvent 1 can be toluene, methyl tertiary butyl ether (MTBE), tetrahydrofuran (THF) (THF), chlorobenzene, methylene dichloride, methyl alcohol, ethanol, Virahol, n-propyl alcohol or propyl carbinol.
Preferably, in step a, the quality of described solvent 1 is feed intake 2～20 times of quality of compound shown in the described formula IV.
Preferably, in step a, the reaction times is 0.5～24 hour.
Preferably, in step b, compound shown in compound shown in the described formula III and formula VIa or the VIb reacts under the condition that alkaline reagents exists, and obtains compound shown in the formula II.Wherein alkaline reagents is used for the acid that the neutralization reaction process generates as catalyzer, promotes the carrying out of reaction; Compound shown in described formula VIa or the VIb (i.e. Ye Tai acyl chlorides or acid anhydrides) can directly be used as reaction solvent.
Preferably, in step b, described alkaline reagents can be yellow soda ash, salt of wormwood, N-methylmorpholine, diazabicylo (DBU), diisopropylethylamine or tri-n-butylamine.
Preferably, in step b, described alkaline reagents: the molar ratio of compound shown in the described formula III is (1.0～15.0): 1.0.
More preferably, in step b, compound shown in compound shown in the described formula III and described formula VIa or the VIb can also react in solvent (solvent 2) under the condition that described alkaline reagents exists, and obtains compound shown in the described formula II.
Preferably, in step b, described solvent 2 can be N, dinethylformamide (DMF), toluene, methyl tertiary butyl ether (MTBE), tetrahydrofuran (THF) (THF), chlorobenzene, methylene dichloride, ethyl acetate, isopropyl acetate, acetate or propionic acid.
Preferably, in step b, the quality consumption of compound shown in described formula VIa or the VIb or described solvent 2 is 1～50 times of compound shown in the described formula III.
Preferably, in step b, temperature of reaction is a reflux temperature; Reaction times is 1～24hr.
Preferably, in step c, compound shown in the described formula II uses alkaline reagents to be hydrolyzed, and reacts in solvent (solvent 3), obtains compound shown in the formula I.
Preferably, in step c, described alkaline reagents can be sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood.
Preferably, in step c, described alkaline reagents: the molar ratio of compound shown in the described formula II is (1.0～5.0): 1.0.
Preferably, in step c, described solvent 3 can be a water; Perhaps water and N, the mixed solvent of dinethylformamide (DMF), methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol, toluene, methyl tertiary butyl ether (MTBE), tetrahydrofuran (THF) (THF), chlorobenzene or methylene dichloride.
Preferably, in step c, the quality consumption of described solvent 3 is 3～50 times of compound shown in the described formula II.
Beneficial effect of the present invention is specially: the synthetic method route is short, is gone on foot by four in the background technology to be reduced to for three steps; Easy and simple to handle, reagent selectivity height, acyl group do not need to slough afterwards earlier in reaction process to add; Production cost is low, is used as the bronsted lowry acids and bases bronsted lowry of reagent for can conveniently obtaining of catalyzer; The product purity height, the yield height has improved 30 percentage points (described method yields in the background technology: 64%, yield of the present invention: more than 88%) nearly than the yield of art methods, be fit to large-scale industrial production, have bigger economic benefit and social benefit.
Embodiment
Content for a better understanding of the present invention is described further below in conjunction with specific embodiment.
Synthetic about step a:
Embodiment 1 (synthesizing of 2-amino-3-(biphenyl-4-yl) methyl propionate salt)
In clean flask, add 4-chloromethyl biphenyl 20.27g (100mmol), N-(diphenylmethyl thiazolinyl) methyl aminoacetate 25.33g (100mmol), toluene 115mL finishes, and temperature is to 0 ℃ in regulating.Splash into the 20%NaOH solution (containing NaOH 4.0g (100.0mmol)) for preparing, drip and finish, insulation 3h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, and insulation is finished, splash into 20% hydrochloric acid soln (containing HCl 5.47g (150.0mmol)), insulation 1h leaves standstill branch vibration layer, organic layer, be evaporated to dried, 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride 24.80g, product yield 85%.
Embodiment 2 (synthesizing of 2-amino-3-(biphenyl-4-yl) methyl propionate salt)
In clean flask, add 4-bromomethylbiphenyl 24.73g (100mmol), N-(diphenylmethyl thiazolinyl) methyl aminoacetate 25.33g (100mmol), chlorobenzene 180mL finishes, and temperature is to 0 ℃ in regulating.Splash into the 20%KOH solution (containing KOH 5.61g (100.0mmol)) for preparing, drip and finish, insulation 2h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, and insulation is finished, splash into 20% formic acid solution (containing formic acid 9.21g (200.0mmol)), insulation 1h leaves standstill branch vibration layer, organic layer, be evaporated to dried, 2-amino-3-(biphenyl-4-yl) methyl propionate formate 26.52g, product yield 88%.
Embodiment 3 (synthesizing of 2-amino-3-(biphenyl-4-yl) methyl propionate oxalate)
In clean flask, add 4-iodomethyl biphenyl 29.41g (100mmol), N-(diphenylmethyl thiazolinyl) methyl aminoacetate 30.40g (120mmol), tetrahydrofuran (THF) 330mL finishes, and temperature is to-5 ℃ in regulating.Splash into the 20%K for preparing
2CO
3Solution (contains K
2CO
327.64g (200.0mmol)), drip and finish, insulation 0.5h.Insulation is finished, splash into water 200mL, be incubated 1h again, insulation is finished, splash into 20% oxalic acid solution (containing oxalic acid 13.50g (150.0mmol)), insulation 1h leaves standstill branch vibration layer, get organic layer, be evaporated to dried, 2-amino-3-(biphenyl-4-yl) methyl propionate oxalate 28.53g, product yield 95%.
Embodiment 4 (synthesizing of 2-amino-3-(biphenyl-4-yl) methyl propionate vitriol)
In clean flask, add 4-p-toluenesulfonyl methyl diphenyl 33.84g (100mmol), N-(diphenylmethyl thiazolinyl) methyl aminoacetate 30.40g (120mmol), N, dinethylformamide (DMF) 180mL finishes, and temperature is to 0 ℃ in regulating.Splash into the 20%KOH solution (containing KOH 11.20g (200.0mmol)) for preparing, drip and finish, insulation 2h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, and insulation is finished, splash into 20% sulphuric acid soln (sulfur acid 14.7g (150mmol)), insulation 1h leaves standstill branch vibration layer, organic layer, be evaporated to dried, 2-amino-3-(biphenyl-4-yl) methyl propionate vitriol 27.39g, product yield 90%.
Embodiment 5 (synthesizing of 2-amino-3-(biphenyl-4-yl) ethyl propionate hydrochloride)
In clean flask, add 4-chloromethyl biphenyl 20.27g (100mmol), N-(diphenylmethyl thiazolinyl) ethyl aminoacetate 28.07g (105mmol), N, dinethylformamide (DMF) 130mL finishes, and temperature is to 0 ℃ in regulating.Splash into the 20%KOH solution (containing KOH 11.2g (199.6mmol)) for preparing, drip and finish, insulation 4h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, and insulation is finished, (hydrochloric 5.47g (150mmol) is incubated 1h, leaves standstill branch vibration layer to splash into 20% hydrochloric acid, organic layer, be evaporated to dried, 2-amino-3-(biphenyl-4-yl) ethyl propionate hydrochloride 28.44g, product yield 93%.
Embodiment 6 (synthesizing of 2-amino-3-(biphenyl-4-yl) ethyl propionate hydrochloride)
In clean flask, add 4-chloromethyl biphenyl 20.27g (100mmol), N-(diphenylmethyl thiazolinyl) ethyl aminoacetate 28.07g (105mmol), N, dinethylformamide (DMF) 130mL finishes, and temperature is to 30 ℃ in regulating.Splash into the 20%KOH solution (containing KOH 11.2g (199.6mmol)) for preparing, drip and finish, insulation 4h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, and insulation is finished, (hydrochloric acid 5.47g (150mmol) is incubated 1h, leaves standstill branch vibration layer to splash into 20% hydrochloric acid, organic layer, be evaporated to dried, 2-amino-3-(biphenyl-4-yl) ethyl propionate hydrochloride 26.61g, product yield 87%.
Embodiment 7 (synthesizing of 2-amino-3-(biphenyl-4-yl) ethyl propionate hydrochloride)
In clean flask, add 4-bromomethylbiphenyl 24.70g (100mmol), N-(diphenylmethyl thiazolinyl) ethyl aminoacetate 28.07g (105mmol), N, dinethylformamide (DMF) 160mL finishes, and temperature is to 5 ℃ in regulating.Splash into the 20%KOH solution (containing KOH 11.2g (199.6mmol)) for preparing, drip and finish, insulation 4h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, and insulation is finished, splash into 20% hydrochloric acid (hydrochloric 5.47g (150mmol)), insulation 1h leaves standstill branch vibration layer, organic layer, be evaporated to dried, 2-amino-3-(biphenyl-4-yl) ethyl propionate hydrochloride 29.05g, product yield 95%.
Embodiment 8 (synthesizing of 2-amino-3-(biphenyl-4-yl) ethyl propionate acetate)
In clean flask, add 4-methylsulfonyl methyl diphenyl 26.23g (100mmol), N-(diphenylmethyl thiazolinyl) ethyl aminoacetate 32.20g (120mmol), methyl alcohol 330mL finishes, and temperature is to 5 ℃ in regulating.Splash into the 20%K for preparing
2CO
3Solution (contains K
2CO
327.64g (200mmol)), drip and finish, insulation 4h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, insulation is finished, and adds 150mL toluene, insulation 1h, leave standstill, branch vibration layer splashes into 20% acetate (containing acetate 30.02g (500mmol)), leave standstill, branch vibration layer gets organic layer, is evaporated to dried, get 2-amino-3-(biphenyl-4-yl) ethyl propionate acetate 30.64g, product yield 93%.
Embodiment 9 (synthesizing of 2-amino-3-(biphenyl-4-yl) propyl propionate tartrate)
In clean flask, add 4-chloromethyl biphenyl 20.27g (100mmol), N-(diphenylmethyl thiazolinyl) Padil propyl ester 42.20g (150mmol), ethanol 520mL finishes, and temperature is to 20 ℃ in regulating.Splash into the 20%Na for preparing
2CO
3Solution (contains Na
2CO
331.8g (300mmol)), drip and finish, insulation 10h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, insulation is finished, add 200mL toluene, splash into 20% tartrate (containing tartrate 75.04g (500mmol)), insulation 1h, leave standstill, branch vibration layer gets organic layer, is evaporated to dried, get 2-amino-3-(biphenyl-4-yl) propyl propionate tartrate hydrochlorate 24.37g, product yield 68%.
Embodiment 10 (synthesizing of 2-amino-3-(biphenyl-4-yl) propyl propionate hydrochloride)
In clean flask, add 4-bromomethylbiphenyl 24.71g (100mmol), N-(diphenylmethyl thiazolinyl) Padil propyl ester 42.20g (150mmol), N, dinethylformamide (DMF) 320mL finishes, and temperature is to 20 ℃ in regulating.Splash into the 20%NaOH solution (containing NaOH8.0g (200mmol)) for preparing, drip and finish, insulation 10h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, and insulation is finished, splash into 20% hydrochloric acid (hydrochloric 7.3g (200mmol)), insulation 1h leaves standstill branch vibration layer, organic layer, be evaporated to dried, 2-amino-3-(biphenyl-4-yl) propyl propionate hydrochloride 23.35g, product yield 73%.
Embodiment 11 (synthesizing of 2-amino-3-(biphenyl-4-yl) isopropyl propionate hydrochloride)
In clean flask, add 4-iodomethyl biphenyl 29.41g (100mmol), N-(diphenylmethyl thiazolinyl) Padil isopropyl ester 42.20g (150mmol), methyl tertiary butyl ether (MTBE) 670mL finishes, and temperature is to 30 ℃ in regulating.Splash into prepare 20%1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU) solution (containing DBU45.67g (300mmol)) drip to be finished, insulation 12h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, and insulation is finished, splash into 20% hydrochloric acid (hydrochloric 18.23g (500mmol)), insulation 1h leaves standstill branch vibration layer, organic layer, be evaporated to dried, 2-amino-3-(biphenyl-4-yl) isopropyl propionate hydrochloride 23.99g, product yield 75%.
Embodiment 12 (synthesizing of 2-amino-3-(biphenyl-4-yl) n-butyl propionate nitrate)
In clean flask, add 4-bromomethylbiphenyl 24.71g (100mmol), N-(diphenylmethyl thiazolinyl) the positive butyl ester 44.31g of Padil (150mmol), N, dinethylformamide (DMF) 210mL finishes, and temperature is to 30 ℃ in regulating.Splash into the 20%KOH solution (containing KOH11.2g (200mmol)) for preparing, drip and finish, insulation 15h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, and insulation is finished, splash into 20% nitric acid (containing nitric acid 12.60g (200mmol)), insulation 1h leaves standstill branch vibration layer, organic layer, be evaporated to dried, 2-amino-3-(biphenyl-4-yl) n-butyl propionate nitrate 27.03g, product yield 75%.
Embodiment 13 (synthesizing of 2-amino-3-(biphenyl-4-yl) isobutyl propionate hydrochloride)
In clean flask, add 4-iodomethyl biphenyl 29.41g (100mmol), N-(diphenylmethyl thiazolinyl) Padil isobutyl ester 59.07g (200mmol), toluene 340mL finishes, and temperature is to 40 ℃ in regulating.Splash into the 20%K for preparing
2CO
3Solution (contains K
2CO
327.64g (200mmol)), drip and finish, insulation 20h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, and insulation is finished, splash into 20% hydrochloric acid (hydrochloric 18.23g (500mmol)), insulation 1h leaves standstill branch vibration layer, organic layer, be evaporated to dried, 2-amino-3-(biphenyl-4-yl) isobutyl propionate hydrochloride 24.04g, product yield 72%.
Embodiment 14 (synthesizing of 2-amino-3-(biphenyl-4-yl) propionic acid tert-butyl ester hydrochloride)
In clean flask, add 4-methylsulfonyl methyl diphenyl 26.23g (100mmol), N-(diphenylmethyl thiazolinyl) Padil tert-butyl ester 59.07g (200mmol), toluene 540mL finishes, and temperature is to 50 ℃ in regulating.Splash into prepare 20%1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU) solution (containing DBU45.67g (300mmol)) drip to be finished, insulation 24h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, and insulation is finished, splash into 20% hydrochloric acid (hydrochloric 18.23g (500mmol)), insulation 1h leaves standstill branch vibration layer, organic layer, be evaporated to dried, 2-amino-3-(biphenyl-4-yl) propionic acid tert-butyl ester hydrochloride 20.03g, product yield 60%.
Embodiment 15 (synthesizing of 2-amino-3-(biphenyl-4-yl) propionic acid benzene methyl hydrochloride)
In clean flask, add 4-bromomethylbiphenyl 24.71g (100mmol), N-(diphenylmethyl thiazolinyl) Padil benzene methyl 39.53g (120mmol), N, dinethylformamide (DMF) 300mL finishes, and temperature is to 0 ℃ in regulating.Splash into the 20%K for preparing
2CO
3Solution (contains K
2CO
327.64g (200mmol)), drip and finish, insulation 4h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, and insulation is finished, splash into 20% hydrochloric acid (hydrochloric 18.23g (500mmol)), insulation 1h leaves standstill branch vibration layer, organic layer, be evaporated to dried, 2-amino-3-(biphenyl-4-yl) propionic acid benzene methyl hydrochloride 32.20g, product yield 91%.
Embodiment 16 (synthesizing of 2-amino-3-(biphenyl-4-yl) propionic acid benzene methyl hydrochloride)
In clean flask, add 4-iodomethyl biphenyl 29.41g (100mmol), N-(diphenylmethyl thiazolinyl) Padil benzene methyl 39.53g (120mmol), toluene 350mL finishes, and temperature is to 0 ℃ in regulating.Splash into the 20%Na for preparing
2CO
3Solution (contains Na
2CO
321.2g (200mmol)), drip and finish, insulation 4h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, and insulation is finished, and splashes into 20% hydrochloric acid (hydrochloric 18.23g (500mmol)), insulation 1h leaves standstill, and branch vibration layer gets organic layer, be evaporated to dried, 2-amino-3-(biphenyl-4-yl) propionic acid benzene methyl hydrochloride 32.55g, product yield 92%.
Embodiment 17 (synthesizing of 2-amino-3-(biphenyl-4-yl) propionic acid benzene methyl hydrochloride)
In clean flask, add 4-p-toluenesulfonyl methyl diphenyl 33.84g (100mmol), N-(diphenylmethyl thiazolinyl) Padil benzene methyl 39.53g (120mmol), toluene 500mL finishes, and temperature is to 0 ℃ in regulating.Splash into prepare 20%1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU) solution (containing DBU45.67g (300mmol)) drip to be finished, insulation 4h.Insulation is finished, and splashes into water 200mL, is incubated 1h again, and insulation is finished, splash into 20% hydrochloric acid (hydrochloric 18.23g (500mmol)), insulation 1h leaves standstill branch vibration layer, organic layer, be evaporated to dried, 2-amino-3-(biphenyl-4-yl) propionic acid benzene methyl hydrochloride 31.85g, product yield 90%.
Synthetic about step b:
Example 18 (synthesizing of 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) ethyl propionate)
In clean flask, add 2-amino-3-(biphenyl-4-yl) ethyl propionate hydrochloride 30.58g (100mmol), toluene 220mL, diacetyl oxide 12.25g (120mmol) is added dropwise to triethylamine 10.62g (105mmol) in the time of 20～30 ℃, drip to finish, reflux, backflow 3h, concentrating under reduced pressure toluene is to doing, add 300mL water, stir 1h, filter, get filter cake and oven dry, get 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) ethyl propionate 26.47g, yield 85%.
Example 19 (synthesizing of 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) ethyl propionate)
In clean flask, add 2-amino-3-(biphenyl-4-yl) ethyl propionate hydrochloride 30.58g (100mmol), acetate 100mL, Acetyl Chloride 98Min. 9.42g (120mmol) is added dropwise to triethylamine 10.62g (105mmol) in the time of 20～30 ℃, drip to finish, reflux, backflow 3h, concentrating under reduced pressure acetate is to doing, add 300mL water, stir 1h, filter, get filter cake and oven dry, get 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) ethyl propionate 28.65g, yield 92%.
Example 20 (synthesizing of 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) ethyl propionate)
In clean flask, add 2-amino-3-(biphenyl-4-yl) ethyl propionate hydrochloride 30.58g (100mmol), Acetyl Chloride 98Min. 78.49g (1000mmol), in the time of 20～30 ℃, be added dropwise to diisopropylethylamine diisopropylethylamine (DIEPA) 13.57g (105mmol), drip and finish reflux, backflow 1h, the concentrating under reduced pressure Acetyl Chloride 98Min. adds 300mL water to doing, and stirs 1h, filter, get filter cake and oven dry, get 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) ethyl propionate 28.65g, yield 92%.
Example 21 (synthesizing of 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) ethyl propionate)
In clean flask, add 2-amino-3-(biphenyl-4-yl) ethyl propionate hydrochloride 30.58g (100mmol), diacetyl oxide 81.67g (800mmol), in the time of 20～30 ℃, be added dropwise to diisopropylethylamine diisopropylethylamine (DIEPA) 12.93g (100mmol), drip and finish reflux, backflow 4h, the concentrating under reduced pressure diacetyl oxide adds 300mL water to doing, and stirs 1h, filter, get filter cake and oven dry, get 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) ethyl propionate 27.40g, yield 88%.
Example 22 (synthesizing of 2-propionamido-3-(biphenyl-4-yl) methyl propionate)
In clean flask, add 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride 29.18g (100mmol), toluene 400mL, diacetyl oxide 13.01g (100mmol) is added dropwise to N-methylmorpholine 30.35g (300mmol) in the time of 20～30 ℃, drip to finish, reflux, backflow 5h, concentrating under reduced pressure toluene is to doing, add 300mL water, stir 5h, filter, get filter cake and oven dry, get 2-propionamido-3-(biphenyl-4-yl) methyl propionate 28.02g, yield 90%.
Example 23 (synthesizing of 2-sec.-propyl formamido group-3-(biphenyl-4-yl) propyl propionate)
In clean flask, add 2-amino-3-(biphenyl-4-yl) propyl propionate hydrochloride 31.98g (100mmol), tetrahydrofuran (THF) 400mL, the different propionyl chloride 21.31g of 2-(200mmol) is added dropwise to K in the time of 20～30 ℃
2CO
341.46g (300mmol), drip to finish, reflux, backflow 15h, concentrating under reduced pressure toluene adds 300mL water to doing, and stirs 1h, filter, filter cake and oven dry, 2-sec.-propyl formamido group-3-(biphenyl-4-yl) propyl propionate 30.04g, yield 85%.
Example 24 (synthesizing of 2-fourth formamido group-3-(biphenyl-4-yl) propionic acid tert-butyl ester)
In clean flask, add 2-amino-3-(biphenyl-4-yl) propionic acid tert-butyl ester hydrochloride 33.39g (100mmol), ethyl acetate 1854mL, propionic anhydride 23.73g (150mmol) is added dropwise to Et in the time of 20～30 ℃
3N 151.79g (1500mmol) drip to finish, reflux, backflow 24h, the concentrating under reduced pressure ethyl acetate adds 300mL water to doing, and stirs 1h, filter, filter cake and oven dry, 2-fourth formamido group-3-(biphenyl-4-yl) propionic acid tert-butyl ester 30.50g, yield 83%.
Example 25 (synthesizing of 2-benzamido-3-(biphenyl-4-yl) ethyl propionate)
In clean flask, add 2-amino-3-(biphenyl-4-yl) ethyl propionate hydrochloride 30.58g (100mmol), tetrahydrofuran (THF) 1000mL, benzoyl oxide 45.25g (200mmol) is added dropwise to Na in the time of 20～30 ℃
2CO
353.00g (500mmol), drip to finish, reflux, backflow 15h, the concentrating under reduced pressure tetrahydrofuran (THF) adds 300mL water to doing, and stirs 1h, filter, filter cake and oven dry, 2-benzamido-3-(biphenyl-4-yl) ethyl propionate 31.00g, yield 80%.
Example 26 (synthesizing of 2-p-chlorobenzamido-3-(biphenyl-4-yl) propionic acid benzene methyl)
In clean flask, add 2-amino-3-(biphenyl-4-yl) propionic acid benzene methyl hydrochloride 35.39g (100mmol), N, dinethylformamide (DMF) 500mL, parachlorobenzoyl chloride 35.00g (200mmol) is added dropwise to triethylamine 20.24g (200mmol) in the time of 20～30 ℃, drip to finish, reflux, backflow 10h, concentrating under reduced pressure N, dinethylformamide (DMF) is to doing, add 300mL water, stir 1h, filter, get filter cake and oven dry, get 2-p-chlorobenzamido-3-(biphenyl-4-yl) propionic acid benzene methyl 41.14g, yield 85%.
Synthetic about step c:
Embodiment 27 (synthesizing of 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid)
In clean flask, add 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) ethyl propionate 31.14g (100mmol), toluene 72mL, water 156mL adds NaOH 4.8g (120mmol), and heats up, in 60 ℃ of insulation reaction 3h, insulation is finished, and splashes into HCl 4.74g (130mmol), drip and finish,, separate out a large amount of solids in 20～30 ℃ of insulations, insulation 2h filters, the filter cake oven dry, get 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid 26.92g, yield 95%.
Embodiment 28 (synthesizing of 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid)
In clean flask, add 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) ethyl propionate 31.14g (100mmol), water 218mL, add NaOH 4.8g (120mmol), and heat up, in 60 ℃ of insulation reaction 3h, insulation is finished, and splashes into HCl 4.74g (130mmol), drips to finish, in 20～30 ℃ of insulations, separate out a large amount of solids, insulation 2h, filter, the filter cake oven dry gets 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid 27.20g, yield 96%.
Embodiment 29 (synthesizing of 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid)
In clean flask, add 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) ethyl propionate 31.14g (100mmol), toluene 72mL, water 156mL adds NaOH 4.12g (103mmol), and heats up, in 60 ℃ of insulation reaction 3h, insulation is finished, and splashes into HCl4.74g (130mmol), drip and finish,, separate out a large amount of solids in 20～30 ℃ of insulations, insulation 2h filters, the filter cake oven dry, get 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid 25.22g, yield 89%.
Embodiment 30 (synthesizing of 2-propionamido-3-(biphenyl-4-yl) propionic acid)
In clean flask, add 2-propionamido-3-(biphenyl-4-yl) methyl propionate 31.14g (100mmol), methyl alcohol 54.8mL, water 50mL adds KOH 5.61g (100mmol), and heats up, in 100 ℃ of insulation reaction 1h, insulation is finished, and splashes into HCl 4.38g (120mmol), drip and finish,, separate out a large amount of solids in 20～30 ℃ of insulations, insulation 2h filters, the filter cake oven dry, get 2-propionamido-3-(biphenyl-4-yl) propionic acid 26.17g, yield 88%.
Embodiment 31 (synthesizing of 2-sec.-propyl formamido group-3-(biphenyl-4-yl) propionic acid)
In clean flask, add 2-sec.-propyl formamido group-3-(biphenyl-4-yl) propyl propionate 35.35g (100mmol), n-propyl alcohol 706.3mL, water 1200mL adds K
2CO
369.1g (500mmol), and heat up, in 70 ℃ of insulation reaction 8h, insulation is finished, splash into HCl 36.46g (1000mmol), drip and finish, in 20～30 ℃ of insulations, separate out a large amount of solids, insulation 2h filters, the filter cake oven dry, get 2-sec.-propyl formamido group-3-(biphenyl-4-yl) propionic acid 28.65g, yield 92%.
Embodiment 32 (synthesizing of 2-butyrylamino-3-(biphenyl-4-yl) propionic acid)
In clean flask, add 2-butyrylamino-3-(biphenyl-4-yl) propionic acid tert-butyl ester 36.75g (100mmol), N, dinethylformamide (DMF) 150mL, water 300mL adds KOH 8.42g (150mmol), and heat up, in 80 ℃ of insulation reaction 24h, insulation is finished, splash into HCl 6.56g (180mmol), drip and finish, in 20～30 ℃ of insulations, separate out a large amount of solids, insulation 2h filters, the filter cake oven dry gets 2-butyrylamino-3-(biphenyl-4-yl) propionic acid 28.34g, yield 91%.
Embodiment 33 (synthesizing of 2-benzamido-3-(biphenyl-4-yl) propionic acid)
In clean flask, add 2-benzamido-3-(biphenyl-4-yl) ethyl propionate 38.75g (100mmol), chlorobenzene 150mL, water 300mL adds KOH 11.22g (200mmol), and heats up, in 10 ℃ of insulation reaction 20h, insulation is finished, and splashes into HCl8.02g (220mmol), drip and finish,, separate out a large amount of solids in 20～30 ℃ of insulations, insulation 2h filters, the filter cake oven dry, get 2-benzamido-3-(biphenyl-4-yl) propionic acid 32.35g, yield 90%.
Embodiment 34 (2-is synthetic to chloro-benzoyl amino-3-(biphenyl-4-yl) propionic acid)
In clean flask, add 2-to chloro-benzoyl amino 4-(biphenyl-4-yl) propionic acid benzene methyl 48.40g (100mmol), chlorobenzene 150mL, water 300mL adds Na
2CO
331.80g (300mmol), and heat up, in 60 ℃ of insulation reaction 10h, insulation is finished, splash into HCl 23.70g (650mmol), drip and finish, in 20～30 ℃ of insulations, separate out a large amount of solids, insulation 2h filters, the filter cake oven dry, get 2-to chloro-benzoyl amino 4-(biphenyl-4-yl) propionic acid 36.63g, yield 93%.
In sum, the invention provides a kind of chemical synthesis process of brand-new 2-acyl amino-3-biphenyl propionic acid.This method route is short, and is easy and simple to handle, the reagent selectivity height, and production cost is low, the product purity height, the yield height is fit to large-scale industrial production, has bigger economic benefit and social benefit.
Need to prove that all documents of mentioning are in the present invention quoted as a reference in this application, are just quoted as a reference separately as each piece document.Should understand in addition, above-described is specific embodiments of the invention and the know-why used, after having read foregoing of the present invention, those skilled in the art can make various changes or modifications and not deviate from spirit of the present invention and scope the present invention, and these equivalent form of values fall within the scope of the invention equally.
Claims (10)
1. the chemical synthesis process suc as formula the acyl amino of the 2-shown in the I-3-biphenyl propionic acid is characterized in that, comprises the steps:
Wherein, X is chlorine, bromine, iodine, methylsulfonyl or p-toluenesulfonyl;
R1 is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl or phenmethyl;
HY is hydrochloric acid, formic acid, acetate, citric acid, oxalic acid, tartrate, sulfuric acid, nitric acid or phosphoric acid;
R2 is methyl, ethyl, propyl group, sec.-propyl, phenmethyl or to chlorophenylmethyl.
2. the chemical synthesis process of 2-acyl amino according to claim 1-3-biphenyl propionic acid is characterized in that: preferred ethyl of described R1 or isobutyl-; The preferred hydrochloric acid of HY; The preferred ethyl of R2.
3. the chemical synthesis process of 2-acyl amino according to claim 1 and 2-3-biphenyl propionic acid is characterized in that: in step a, basic solution is sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood or diazabicylo solution; Described alkali: mole proportioning that feeds intake of compound shown in the formula IV is (1.0～3.0): 1.0.
4. the chemical synthesis process of 2-acyl amino according to claim 1-3-biphenyl propionic acid is characterized in that: described HY acidic substance: mole proportioning that feeds intake of compound shown in the formula IV is (1.0～5.0): 1.0.
5. the chemical synthesis process of 2-acyl amino according to claim 1 and 2-3-biphenyl propionic acid is characterized in that: in step a, temperature of reaction is-5～50 ℃.
6. the chemical synthesis process of 2-acyl amino according to claim 1-3-biphenyl propionic acid, it is characterized in that: in step b, compound shown in compound shown in the formula III and formula VIa or the VIb reacts under the condition that alkaline reagents exists, and obtains compound shown in the formula II; Described alkaline reagents is yellow soda ash, salt of wormwood, N-methylmorpholine, diazabicylo, diisopropylethylamine or tri-n-butylamine.
7. the chemical synthesis process of 2-acyl amino according to claim 6-3-biphenyl propionic acid is characterized in that: in step b, described alkaline reagents: the molar ratio of compound shown in the described formula III is (1.0～15.0): 1.0.
8. according to the chemical synthesis process of claim 6 or 7 described 2-acyl amino-3-biphenyl propionic acids; it is characterized in that: compound shown in compound shown in the described formula III and described formula VIa or the VIb is under the condition that described alkaline reagents exists; can also in organic solvent, react, obtain compound shown in the described formula II.
9. the chemical synthesis process of 2-acyl amino according to claim 8-3-biphenyl propionic acid; it is characterized in that: in step b; described organic solvent is N, dinethylformamide, toluene, methyl tertiary butyl ether, tetrahydrofuran (THF), chlorobenzene, methylene dichloride, ethyl acetate, isopropyl acetate, acetate or propionic acid.
10. according to the chemical synthesis process of claim 1 or 9 described 2-acyl amino-3-biphenyl propionic acids, it is characterized in that: in step b, the quality consumption of compound or described organic solvent shown in formula VIa or the VIb is 1～50 times of compound shown in the formula III.
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