CN1207275C - Chiral compound (S)-(+)- and (R)-(-)-3-alkylamido-3-carboxy-1-phenyl propanone and prep. thereof - Google Patents
Chiral compound (S)-(+)- and (R)-(-)-3-alkylamido-3-carboxy-1-phenyl propanone and prep. thereof Download PDFInfo
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- CN1207275C CN1207275C CN 00134049 CN00134049A CN1207275C CN 1207275 C CN1207275 C CN 1207275C CN 00134049 CN00134049 CN 00134049 CN 00134049 A CN00134049 A CN 00134049A CN 1207275 C CN1207275 C CN 1207275C
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- anhydride
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- chipal compounds
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Abstract
The present invention relates to chiral compounds(S)-(+)-and (R)-(-)-3-alkylamino-3-carboxyl-1-propiophenone and a preparation process thereof.
Description
The present invention relates to the chipal compounds (S)-(+) of following formula-and (R)-(-)-3-alkyl amido-3-carboxyl-1-Propiophenone (1) and preparation method thereof:
Wherein R represents hydrogen, C
1-C
9Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Haloalkyl, C
1-C
4Halo oxygen base.
This compound can be used for preparing chiral alpha-non-natural amino acid--the critical materials of L-and D-(3-replacement) hyperphenylalaninemia and derivative thereof, and L-and D-(3-replacement) hyperphenylalaninemia and derivative thereof are the important source material of preparation Angiotensin (ACE) inhibitor class medicine.
Do not see the report of this compounds in the document, reason is that this type of use of a compound is further developed, and particularly L-and D-(3-replacement) hyperphenylalaninemia and the effect of derivative in medicines structure thereof are big more along with various non-natural chiral amino acids in recent years.Therefore, seeking a suitable path of preparing has chiral compound with high optical purity (1) and then becomes extremely important.
Purpose of the present invention is exactly to seek the method that a suitable suitability for industrialized production prepares the 3-amino-3-carboxyl-1-Propiophenone (1) of high-optical-purity.In this method, compound (1) need not resolving and purifying again can obtain (the S)-type of high-optical-purity and (R)-type optical isomer.
The present invention realizes by following two-step reaction: (a) in the presence of thinner, with L-type or D-type aspartic acid and acylating reagent reaction, form N-alkane acyl aspartoyl inner-acid anhydride (3); (b) (3) carry out the Friedel-Crafts reaction with benzene under the Lewis acid effect, obtain this compound (1) after hydrolysis.Concrete reaction process is as follows:
2(L)-(+)- 3(S)-(-)- 1(S)-(+)-
2(D)-(-)- 3(R)-(+)- 1(R)-(-)-
Wherein R represents hydrogen, C
1-C
9Alkyl, C
1-C
1Alkoxyl group, C
1-C
1Haloalkyl.
Reactions steps (a) is acylation reaction preparation formula (a 3) compound.This reaction is in the presence of suitable thinner, selects fatty acid anhydride or fatty acyl halogenation as acylating reagent, and fatty acid anhydride or fatty carboxylic acid halides can be the fatty acid anhydrides of 1-10 carbon; The halo fatty acyl acid anhydride of the alkoxyl group fatty acid anhydride of 1-5 carbon, a 1-5 carbon; Or fatty carboxylic acid halides, alkoxyl group fat carboxylic acid halides, halo fat carboxylic acid halides.The preferred C of fatty acid anhydride
1-C
1Fatty acid anhydride such as formic anhydride, diacetyl oxide, propionic anhydride, butyryl oxide, methoxyacetic acid acid anhydride, sym-dichloroacetic anhydride or mixed acid anhydride, the preferred C of fatty carboxylic acid halides
1-C
3Fat carboxylic acid halides such as formyl chloride, Acetyl Chloride 98Min., propionyl chloride, chloracetyl, methoxyacetyl chloride.When carrying out reactions steps of the present invention (a), adopt a large amount of relatively acylating reagents usually, for example the acylating reagent consumption is generally 2-20 doubly to the aspartic acid amount.Temperature of reaction generally is controlled at 0-150 ℃, preferred 60-110 ℃.
The thinner that is fit to is suitable for the inert organic solvents of this acylation reaction.These materials comprise particularly aliphatics or alicyclic optional halogenated hydrocarbon, such as, for example sherwood oil, hexane, hexanaphthene, heptane, methylene dichloride, ethylene dichloride, chloroform, tetracol phenixin; Ethers is as ether, diisopropyl ether, dioxan, tetrahydrofuran (THF) or glycol dimethyl ether, ethylene glycol diethyl ether; Ketone is as acetone, butanone or mibk; Nitrile is as acetonitrile, propionitrile, butyronitrile; The ester class is as methyl acetate or ethyl acetate; The mixture of they and water, or water.
Reactions steps (b) is to adopt the Friedel-Crafts reaction, and formula (3) preparation formula (1) chipal compounds is arranged.If reactions steps (b) is carried out in the presence of Lewis acid in the benzene system, adopting Lewis acid is aluminum trihalide such as aluminum chloride, alchlor, three iron halide such as ferric bromide.Lewis acidic consumption is 2-8 a times of compound (3), and preferred 2.5-5.5 doubly.Temperature of reaction generally is controlled at 10-100 ℃, preferred 20-70 ℃.Reaction times is less to this reaction influence, can be in the range of broad general 2-60 hour, and preferred 10-40 hour.
Reaction mass is poured in frozen water-hydrochloric acid, and the hydrolysis after-filtration can obtain the khaki color solid, is compound (1).
Method of the present invention is normally carried out under normal pressure.Yet, the inventive method also can the pressurization or the decompression under _ _ normally 0.1 the crust to 10 the crust between pressure under carry out.
Collection be with ordinary method carry out (referring to, the preparation embodiment).
Chipal compounds 3-amino-3-carboxyl-1-Propiophenone (1) is a kind of important medicine intermediate, for example working as chipal compounds (1) is the L-type, when the 3-substituted radical is hydrogen, be L-hyperphenylalaninemia (L-HPA), it is that the present world is the common raw material of about 15 kinds of antihypertensive agents, for example can be directly used on the one hand and make Benazepril.HCl, Lisinopril.HCl, Temocapril.HCl, Cliazapril.HCl etc. can make multiple antihypertensive drug such as Sprirapril.HCl, Delapril by making bimonthly peptide compounds (MEPA) on the other hand, Imidapril.HCl, Quinapril etc.
Following examples are intended to help to understand and explanation the present invention, but not limit the scope of the invention.
Embodiment 1: step (a) (S)-(-)-preparation of N-ethanoyl aspartoyl intramolecular anhydride (3)
In the 1000ml four-hole bottle of agitator, reflux condensing tube and dropping funnel is housed, add 80g L-aspartic acid, 500ml water stirs and is warming up to 100 ℃, Dropwise 5 00ml diacetyl oxide, reaction solution becomes clear, stirs 6 hours.The decompression precipitation adds the 500ml diacetyl oxide again to doing, and heat temperature raising to 100 ℃ is incubated 30 minutes.The decompression precipitation obtains the 95g title compound to doing, and is white solid, yield 95.4%.
[α]
D 25=-51.33 ° (c=1, acetone)
1H-NMR(300MHz，DMSO，ppm)：1.85(s，3H，-CH
3)，2.21-3.24(m，2H，-CH
2)，4.57(m，1H，-CH)，8.83(s，1H，-NH)。
Embodiment 2: step (a) (S)-(-)-preparation of N-propionyl aspartoyl intramolecular anhydride (3)
In the 500ml four-hole bottle of agitator, reflux condensing tube and dropping funnel is housed, add 40g L-aspartic acid, 100ml ethylene dichloride, frozen water are cooled to 5 ℃, and Dropwise 5 0ml propionyl chloride stirred 6 hours.The decompression precipitation adds the 400ml propionic anhydride again to doing, and heat temperature raising to 100 ℃ is incubated 30 minutes.The decompression precipitation obtains the 70g title compound to doing, and is white solid, yield 75%.
[α]
D 25=-46.52 ° (c=1, acetone)
Embodiment 3: step (a) (S)-(-)-preparation of N-butyryl radicals aspartoyl intramolecular anhydride (3)
In the 500ml four-hole bottle of agitator, reflux condensing tube and dropping funnel is housed, add 40g L-aspartic acid, 100ml water stirs and is warming up to 100 ℃, drips the 200ml butyryl oxide, and reaction solution becomes clarification, and is transparent, stirs 6 hours.The decompression precipitation adds the 300ml diacetyl oxide again to doing, and heat temperature raising to 105 ℃ is incubated 30 minutes.The decompression precipitation obtains the 90g title compound to doing, and is white solid, yield 90%.
[α]
D 25=-40.52 ° (c=1, acetone)
Embodiment 4: step (a) (R)-(+)-preparation of N-formyl radical aspartoyl intramolecular anhydride (3)
In the 500ml four-hole bottle of agitator, reflux condensing tube and dropping funnel is housed, add the 40gD-aspartic acid, the 100ml ethyl acetate, under the stirring at room, Dropwise 5 0ml formyl chloride adds and closes, and stirs 6 hours.The decompression precipitation adds the 300ml diacetyl oxide again to doing, and heat temperature raising to 105 ℃ is incubated 30 minutes.The decompression precipitation obtains the 90g title compound to doing, and is white solid, yield 90%.
[a]
D 25=-49.52 ° (c=1, acetone)
Embodiment 5: step (b) (S)-(+)-preparation of 3-acetylaminohydroxyphenylarsonic acid 3-carboxyl-1-Propiophenone (1)
In the 3000mL there-necked flask, throw 2000ml benzene, 280g aluminum chloride and 67g (S)-(-)-N-ethanoyl aspartoyl intramolecular anhydride (3) stirred 36 hours, formed thick thing.
Reaction mass is poured in 2000g ice and the 400ml concentrated hydrochloric acid mixing solutions, stirred 1 hour.Filter, obtain the khaki color solid, 60-70 ℃ of oven dry obtains the 100g title compound thus, yield 98.5%.
[a]
D 25=63.50 ° (c=0.3, acetone), content (HPLC): 99.5%.
1H-NMR(300MHz.DMSO，ppm)：1.82(s，3H，-CH
3)，3.43(m，2H，-CH
2)，4.75(m，1H，-CH)，7.55-7.95(m，SH，-C
6H
5)，8.20(d，2H，-NH，-COOH)
Embodiment 6: step (b) (S)-(+)-preparation of 3-formamido group 3-carboxyl-1-Propiophenone (1)
In the 500ml there-necked flask, throw 300ml benzene, 30g ferric bromide and 21g (S)-(-)-N-formyl radical asparagus fern acyl intramolecular anhydride (3) is warming up to 40-60 ℃; stirred 2 hours, and threw the 30g ferric bromide, stirred 2 hours; throw the 30g ferric bromide again, stirred 10 hours, form thick thing.
Reaction mass is poured in 300g ice and the 100ml concentrated hydrochloric acid mixing solutions, stirred 1 hour.Filter, obtain the khaki color solid, 50-60 ℃ of oven dry obtains the 25g title compound thus, yield 79.6%.
[α]
D 25=58.90 ° (c=0.3, acetone)
Embodiment 7: step (b) (S)-(+)-preparation of 3-butyrylamino-3-carboxyl-1-Propiophenone (1)
In the 3000mL there-necked flask, throw 2500ml benzene, 50g aluminum chloride and 60g (S)-(-)-N-butyryl radicals aspartoyl intramolecular anhydride (3) is warming up to 70 ℃, stirs 2 hours, throws the 50g aluminum chloride every 2 hours, throws 250g altogether, stirs 10 hours, forms thick thing.
Reaction mass is poured in 1500g ice and the 250ml concentrated hydrochloric acid mixing solutions, stirred 1 hour.Filter, obtain the khaki color solid, 60-70 ℃ of oven dry obtains the 80g title compound thus, yield 85%.
[α]
D 25=47.0 ° (c=0.3, acetone)
Embodiment 8: step (b) (R)-(-)-preparation of 3-acetylaminohydroxyphenylarsonic acid 3-carboxyl-1-Propiophenone (1)
In the 500mL there-necked flask, throw 350ml benzene, 100g alchlor and 25g (R)-(+)-N-ethanoyl asparagus fern acyl intramolecular anhydride (3) refluxes and stirred 12 hours.
Reaction mass is poured in 500g ice and the 300ml concentrated hydrochloric acid mixing solutions, stirred 3 hours, filter, obtain the khaki color solid, obtain the 35g title compound thus, yield 93.5%.
[α]
D 25=-60.50 ° (c=0.3, acetone)
Claims (10)
1. a following formula (1) chipal compounds:
Wherein
R represents hydrogen, C
1-C
9Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Haloalkyl.
2. according to formula (1) chipal compounds of claim 1, wherein R represents hydrogen, methyl, ethyl, propyl group.
3. the method for a preparation formula (1) chipal compounds, this method comprises following reactions steps:
(a). in the presence of thinner, L-or D-aspartic acid (2) are carried out acylation reaction with acylating reagent, generation (S)-(-)-or (R)-(+)-N-alkyloyl aspartoyl intramolecular anhydride (3);
(b). (3) and benzene carry out the Friedel-Crafts reaction in the presence of Lewis acid then, generate compound (1) after hydrolysis.
4. according to the method for claim 3, wherein, thinner can be water or organic solvent in the step (a).
5. according to arbitrary method of claim 3 to 4, wherein said acylating reagent is fatty acid anhydride or fatty carboxylic acid halides.
6. according to the method for claim 5, wherein acylating reagent is selected from formic anhydride, diacetyl oxide, propionic anhydride, butyryl oxide, formyl chloride, Acetyl Chloride 98Min. or propionyl chloride.
7. according to the method for claim 3, the acylation reaction temperature is 0-150 ℃.
8. according to the method for claim 3, the Lewis acid that adopts in the Friedel-Crafts reaction is aluminum trihalide or three iron halide.
9. according to the method for claim 3, the temperature of Friedel-Crafts reaction is 10-100 ℃, and the reaction times is 2-60 hour.
10. chipal compounds (1) is used to prepare the application of chirality L-and D-(3-replacement) hyperphenylalaninemia and derivative thereof.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00134049 CN1207275C (en) | 2000-12-08 | 2000-12-08 | Chiral compound (S)-(+)- and (R)-(-)-3-alkylamido-3-carboxy-1-phenyl propanone and prep. thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00134049 CN1207275C (en) | 2000-12-08 | 2000-12-08 | Chiral compound (S)-(+)- and (R)-(-)-3-alkylamido-3-carboxy-1-phenyl propanone and prep. thereof |
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| Publication Number | Publication Date |
|---|---|
| CN1357537A CN1357537A (en) | 2002-07-10 |
| CN1207275C true CN1207275C (en) | 2005-06-22 |
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| CN 00134049 Expired - Fee Related CN1207275C (en) | 2000-12-08 | 2000-12-08 | Chiral compound (S)-(+)- and (R)-(-)-3-alkylamido-3-carboxy-1-phenyl propanone and prep. thereof |
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Granted publication date: 20050622 Termination date: 20100108 |