CN111825563A - Preparation method of beta-homoglutamic acid - Google Patents
Preparation method of beta-homoglutamic acid Download PDFInfo
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- CN111825563A CN111825563A CN202010624692.2A CN202010624692A CN111825563A CN 111825563 A CN111825563 A CN 111825563A CN 202010624692 A CN202010624692 A CN 202010624692A CN 111825563 A CN111825563 A CN 111825563A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/02—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from isocyanates with formation of carbamate groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
The invention belongs to the field of preparation of organic compounds. The invention provides a preparation method of beta-homoglutamic acid. The method is characterized in that 3-cyclohexene carboxylic acid is used as a raw material, and the beta-homoglutamic acid is synthesized with high yield through three-step reactions of Curtius rearrangement, olefin oxidation and protective group removal, and the optically pure 3-cyclohexene carboxylic acid can be used for configuration maintenance to obtain the high-yield and high-optically pure beta-homoglutamic acid. The method has the advantages of easily available raw materials, mild reaction conditions and low cost, and is suitable for large-scale preparation of the beta-homoglutamic acid.
Description
Technical Field
The invention belongs to the field of preparation of organic compounds. The present invention relates to a process for producing beta-homoglutamic acid.
Background
Beta-homoglutamic acid is a very important non-natural beta-amino acids, and is widely applied to synthesis of new peptide drugs and development of nano materials in recent years, and research on a synthesis method of the beta-homoglutamic acid is gradually paid attention to. At present, the following two strategies are mainly used for preparing the optically pure beta-homoglutamic acid: one is chiral-induced synthesis by using an optically pure chiral auxiliary reagent, such as an optically pure 2-tert-butylperhydropyrimidone induction method (j.am.chem.soc.1996,118,8727) reported by snickus and a D-gulose-derived hydroxylamine induction method (chem.sci.2010,1,637.) developed by Bode, and although this strategy can successfully prepare a plurality of beta-aminoacids including chiral beta-homoglutamic acid, the chiral induction reagent used in the method is not easy to obtain, and the preparation is complex and high in cost; the other strategy is to react L-glutamic acid as a starting material with diazomethane at low temperature to synthesize diazoketone, and then rearrange the diazoketone to obtain beta-homoglutamic acid (Tetrahedron 2000,56, 9739; J.Org.chem.1999,64,2176; J.Med.chem.1990,33,2734). The scheme has the advantages of easily available raw materials, low cost, high optical purity of products and universal adoption, but because the dangerous diazomethane is used, low-temperature reaction is needed, and amplification is not suitable. Therefore, the development of a new method for preparing beta-homoglutamic acid, particularly optically pure beta-homoglutamic acid, with simplicity, high efficiency and low cost has important significance for the development of polypeptide drugs and the synthesis of nano materials.
Disclosure of Invention
The invention aims to develop a method for preparing beta-homoglutamic acid, which is simple, efficient, mild in condition and low in cost.
The invention is characterized in that: the method takes 3-cyclohexene carboxylic acid as a raw material, and synthesizes the beta-homoglutamic acid with high yield through three steps of Curtius rearrangement, olefin oxidation and protective group removal, and the optically pure 3-cyclohexene carboxylic acid can be used for configuration maintenance to obtain the high-yield and high-optically pure beta-homoglutamic acid.
The beta-homoglutamic acid synthesized by the invention is characterized in that: represented by the formula
The invention adopts the following technical scheme:
1) taking 3-cyclohexenecarboxylic acid (1) as a raw material, firstly adding diphenyl phosphorazide, carrying out Curtius rearrangement to obtain isocyanate, and then adding benzyl alcohol or tert-butyl alcohol or fluorenylmethanol to carry out one-pot reaction to generate cyclohexenylcarbamic acid benzyl ester (2a), cyclohexenylcarbamic acid tert-butyl ester (2b) or cyclohexenylcarbamic acid fluorenylmethyl ester (2 c). Optically pure intermediate 2 with corresponding configuration is obtained by using optically pure 1 as a raw material.
2) And (3) carrying out olefin oxidative cracking on the 2-form copolymer by using potassium permanganate to obtain a diacid intermediate (3).
3) Removing the protecting group Cbz or Boc or Fmoc from the 3 to obtain the beta-homoglutamic acid (4). Initially, L-4 was obtained using S-form 1 as the starting material, and D-4 was obtained using R-form 1 as the starting material.
Detailed Description
(1) Process for preparing racemic beta-homoglutamic acid
The synthesis of racemic beta-homoglutamic acid adopts racemic 3-cyclohexenecarboxylic acid as a raw material, acyl azide is synthesized by utilizing diphenylphosphorylazide, isocyanate is obtained by Curtius rearrangement, then benzyl alcohol or tert-butyl alcohol or fluorene methanol is added for one-pot reaction to generate cyclohexenyl carbamic acid benzyl ester or cyclohexenyl carbamic acid tert-butyl ester or cyclohexenyl carbamic acid fluorene methyl ester, then potassium permanganate is used for carrying out olefin oxidative cracking to obtain a diacid intermediate, and finally, a protecting group Cbz or Boc or Fmoc is removed to obtain the racemic beta-homoglutamic acid.
The solvent used in Curtius rearrangement reaction is toluene and xylene, and the reaction temperature is 100-140 ℃.
(2) Preparation method of optically pure beta-homoglutamic acid
The invention adopts optically pure 3-cyclohexenecarboxylic acid as raw material to obtain optically pure beta-homoglutamic acid, uses S-type 3-cyclohexenecarboxylic acid as raw material to obtain L-beta-homoglutamic acid, and uses R-type 3-cyclohexenecarboxylic acid as raw material to obtain D-beta-homoglutamic acid.
Example of the implementation
The present invention will be described in detail below with reference to examples. However, the present invention is not limited to the embodiments shown in the embodiments, and the specific embodiments may be variously modified within the scope of the description of the specific embodiments of the present invention.
Preparation of 1 racemic β -homoglutamic acid (1)
10g of racemic 3-cyclohexenecarboxylic acid was dissolved in 100ml of toluene, 8.9g of triethylamine was added dropwise under nitrogen protection, and the mixture was stirred at room temperature for 30 minutes, then 23.1g of diphenylphosphoryl azide was slowly added dropwise, and stirring was continued for 1.5 hours after the addition. The temperature is raised to 110 ℃, and the reaction is kept for 3 hours. 9.5g of benzyl alcohol were added dropwise and the reaction was continued at 110 ℃ for 12 hours. Cooling to room temperature, adding 100ml saturated sodium bicarbonate water solution, separating organic layer, extracting water phase with ethyl acetate, mixing organic phases, washing with saturated saline water, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain crude productThe crude product was recrystallized from ethyl acetate/n-hexane to give benzyl cyclohexenylcarbamate 2a as a white solid, 14.5g (80%). mp 58-61 ℃.1H NMR(400MHz,CDCl3):＝7.26-7.37(m,5H),5.57-5.69(m,2H),5.10(s,2H),4.80(s,1H),3.88(s,1H),2.37-2.42(m,1H), 2.07-2.20(m,2H),1.84-1.94(m,2H),1.52-1.61(m,1H).13C NMR(100MHz, CDCl3):＝155.7,136.6,128.5,128.2,128.1,127.0,124.3,66.5,46.2,31.9,28.3, 23.5.
10g of the intermediate 2a is dissolved in 500mL of acetone, 250mL of 0.5M potassium permanganate aqueous solution is slowly dropped, the reaction is continued at room temperature after the completion of the addition, and TLC is used for tracking until the reaction is completed. Adding sodium thiosulfate to quench excessive potassium permanganate, adjusting the pH of the solution to be less than 2 by using 3M hydrochloric acid, and continuing stirring for 20 min. The acetone was distilled off under reduced pressure, the aqueous phase was extracted three times with 250mL of ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product 3a 11.5g (90%) as a white solid. mp 158-.1H NMR(400MHz,DMSO):＝12.14(s,2H),7.29-7.38(m,5H),7.22(d,J＝8.6 Hz,1H),5.00(s,2H),3.75-3.86(m,1H),2.34-2.40(m,2H),2.20(t,J＝7.5Hz,2H), 1.67-1.79(m,1H),1.52-1.63(m,1H).13C NMR(100MHz,DMSO):＝174.6, 172.8,156.1,137.7,128.8,128.2,128.1,65.6,47.9,40.0,30.7,29.9.
10g of intermediate 3a was dissolved in 100ML methanol, 0.5g of 10% Pd/C was added, and after hydrogen substitution, at 15psi H2Reacting at room temperature for 10h, filtering out the catalyst after reaction, and concentrating under reduced pressure to obtain racemic beta-homoglutamic acid 4, 5.33g of white solid with the yield of 98%.1H NMR(400MHz,D2O)：＝3.50-3.54 (m,1H),2.59-2.63(m,1H),2.39-2.51(m,3H),1.86-1.93(m,2H).13C NMR(100 MHz,D2O):＝178.3,176.7,48.5,37.4,30.9,27.6。
Preparation of 2-racemic β -homoglutamic acid (2)
20g of racemic 3-cyclohexenecarboxylic acid is dissolved in 150ml of toluene, 17.8 g of triethylamine is added dropwise under the protection of nitrogen, then the mixture is stirred for 40 minutes at room temperature, 46.2g of diphenylphosphoryl azide is slowly added dropwise, and the stirring is continued for 2 hours after the addition. The temperature is raised to 110 ℃, and the reaction is kept for 3 hours. 13g of tert-butanol was added and the reaction was continued for 24 hours while raising the temperature to 100 ℃. Cooling to room temperature, adding 100ml saturated sodium bicarbonate aqueous solution, separating organic layer, extracting water phase with ethyl acetate, mixing organic phase, washing with saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain crude product 23g cyclohexenyl carbamic acid tert-butyl ester 2 b.
And (3) dissolving the crude product 2b in 800mL of acetone, slowly dropwise adding 500mL of 0.5M potassium permanganate aqueous solution, continuing the reaction at room temperature after the addition is finished, and tracking by TLC until the reaction is complete. Adding sodium thiosulfate to quench excessive potassium permanganate, adjusting the pH of the solution to be less than 2 by using 3M hydrochloric acid, and continuing stirring for 20 min. The acetone was distilled off under reduced pressure, the aqueous phase was extracted three times with 500mL of ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 3 b.
Intermediate 3b was added to 100mL of dichloromethane, 10mL of trifluoroacetic acid was added dropwise under ice bath, and the mixture was allowed to warm to room temperature overnight. Concentrating under reduced pressure to dryness to obtain trifluoroacetate of racemic beta-homoglutamic acid 4, then adding ethanol, dripping equivalent triethylamine, precipitating solid, filtering and drying to obtain 418 g of racemic beta-homoglutamic acid.
Preparation of 3-racemic β -homoglutamic acid (3)
10g of racemic 3-cyclohexenecarboxylic acid is dissolved in 100ml of xylene, 8.9g of triethylamine is added dropwise under the protection of nitrogen, then the mixture is stirred for 30 minutes at room temperature, 23.1g of diphenyl phosphorazidate is slowly added dropwise, and the stirring is continued for 1.5 hours after the addition. The temperature is raised to 110 ℃, and the reaction is kept for 3 hours. 17.2g of fluorenylmethanol were added and the reaction was continued for 12 hours while the temperature was raised to 140 ℃. Cooling to room temperature, adding 100ml saturated sodium bicarbonate aqueous solution, separating organic layer, extracting water phase with ethyl acetate, mixing organic phase, washing with saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain crude product 22g cyclohexenyl carbamic acid fluorene methyl ester 2 c.
The crude product 2c is dissolved in 500mL of acetone, 250mL of 0.5M aqueous potassium permanganate solution is slowly added dropwise, the reaction is continued at room temperature after the addition is finished, and TLC tracking is carried out until the reaction is complete. Adding sodium thiosulfate to quench excessive potassium permanganate, adjusting the pH of the solution to be less than 2 by using 3M hydrochloric acid, and continuing stirring for 20 min. The acetone was distilled off under reduced pressure, the aqueous phase was extracted three times with 250mL of ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 3 c.
And adding the intermediate 3c into DMF containing 20% piperidine, stirring at room temperature for 2 hours, performing reaction, performing reduced pressure concentration to remove piperidine and DMF, and purifying a crude product by using ion exchange resin to obtain racemic beta-homoglutamic acid 4 and 9.8g of a white solid.
Preparation of 4L-beta-homoglutamic acid
By the method of example 1, S-2a, a white solid, with a yield of 77%, mp58-59 ℃, and [ alpha ], was obtained from S-3-cyclohexenecarboxylic acid as a raw material]D 30-26.4(c 1.0, MeOH). Oxidizing the S-2a by potassium permanganate to obtain S-3a, wherein the optical purity of the crude product is 95 percent, the optical purity of the ethyl acetate/petroleum ether is recrystallized once, the optical purity is more than 99 percent, the yield is 88 percent, the temperature is 183 ℃ under mp 182-]D 30-9.8(c 1.0, MeOH). The protective group of the S-3a is removed by catalytic hydrogenation to obtain L-beta-homoglutamic acid as white solid with the yield of 98 percent and the temperature of mp 188-]D 30＝+30.7(c 0.4, H2O)。
Preparation of 5D-beta-homoglutamic acid
By the method of example 1, R-2a is obtained as a white solid with a yield of 79% from R-3-cyclohexenecarboxylic acid as a raw material, mp55-58 ℃ and [ alpha ]]D 30+26.4(c 1.0, MeOH). Oxidizing R-2a by potassium permanganate to obtain R-3a, wherein the optical purity of the crude product is 95 percent, the optical purity of the ethyl acetate/petroleum ether is recrystallized once, the yield is 87 percent, the temperature is 183 ℃ under mp 182-]D 30+10.0(c 1.0, MeOH). The R-3a is subjected to catalytic hydrogenation to remove the protecting group to obtain D-beta-homoglutamic acid as white solid with the yield of 97 percent and the temperature of mp 190-]D 30＝-36(c 0.4, H2O)。
Claims (3)
1. A method for preparing beta-homoglutamic acid is characterized in that: the method takes 3-cyclohexene carboxylic acid as a raw material, and synthesizes the beta-homoglutamic acid with high yield through three steps of Curtius rearrangement, olefin oxidation and protective group removal, and the optically pure 3-cyclohexene carboxylic acid can be used for configuration maintenance to obtain the high-yield and high-optically pure beta-homoglutamic acid.
2. The Curtius rearrangement reaction used in the method for synthesizing β -homoglutamic acid according to claim 1, characterized in that: firstly adding diphenyl phosphorazide, then adding benzyl alcohol, tert-butyl alcohol or fluorenylmethanol for one-pot reaction to generate cyclohexenyl benzyl carbamate, tert-butyl cyclohexenyl carbamate or fluorenylmethyl carbamate, wherein the used solvents are toluene and xylene, and the reaction temperature is 100-140 ℃.
3. The method for synthesizing optically pure β -homoglutamic acid according to claim 1, wherein: the L-beta-homoglutamic acid is synthesized by taking (S) -3-cyclohexenecarboxylic acid as a raw material, and the D-beta-homoglutamic acid can be synthesized by taking (R) -3-cyclohexenecarboxylic acid as a raw material.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001030745A1 (en) * | 1999-10-25 | 2001-05-03 | Fujisawa Pharmaceutical Co., Ltd. | Anthranilic acid derivatives as inhibitors of the cgmp-phosphodiesterase |
| WO2005005633A2 (en) * | 2003-07-10 | 2005-01-20 | Pharmacia Corporation | Methods for the stereoselective synthesis and enantiomeric enrichment of b-amino acids |
| CN101857575A (en) * | 2009-04-07 | 2010-10-13 | 上海合全药业有限公司 | Industrial preparation method of 5-methylpyrazin-2-amine |
| CN102827064A (en) * | 2012-08-14 | 2012-12-19 | 华东师范大学 | Synthetic method for aza-bicyclo octane[3.3.0] derivatives |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001030745A1 (en) * | 1999-10-25 | 2001-05-03 | Fujisawa Pharmaceutical Co., Ltd. | Anthranilic acid derivatives as inhibitors of the cgmp-phosphodiesterase |
| WO2005005633A2 (en) * | 2003-07-10 | 2005-01-20 | Pharmacia Corporation | Methods for the stereoselective synthesis and enantiomeric enrichment of b-amino acids |
| CN101857575A (en) * | 2009-04-07 | 2010-10-13 | 上海合全药业有限公司 | Industrial preparation method of 5-methylpyrazin-2-amine |
| CN102827064A (en) * | 2012-08-14 | 2012-12-19 | 华东师范大学 | Synthetic method for aza-bicyclo octane[3.3.0] derivatives |
Non-Patent Citations (8)
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