CN117417272A - Preparation method of Boc-D-isoleucine - Google Patents

Preparation method of Boc-D-isoleucine Download PDF

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CN117417272A
CN117417272A CN202311355939.5A CN202311355939A CN117417272A CN 117417272 A CN117417272 A CN 117417272A CN 202311355939 A CN202311355939 A CN 202311355939A CN 117417272 A CN117417272 A CN 117417272A
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compound
boc
isoleucine
bromoacetate
producing
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孙开�
程兴洋
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Shanghai Haigao Technology Co ltd
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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
    • C07C269/04—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 amines with formation of carbamate groups
    • 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
    • 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
    • C07C269/06—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a preparation method of Boc-D-isoleucine, belonging to the field of medical intermediates. Phenyl oxazolidone and bromoacetate are taken as raw materials, and are aminated under the action of strong alkali to generate a compound A; then esterifying the mixture with crotyl alcohol to generate a compound B; then dehydrogenating under the action of a lithium reagent, generating a claisen rearrangement to generate a compound C, dissociating trimethylchlorosilane to obtain a compound D, and hydrolyzing hydrochloric acid to obtain a compound E; finally, the catalytic hydrogenation addition and Boc protection are carried out simultaneously to obtain Boc-D-isoleucine. The preparation method has the advantages of easily obtained raw materials, high total yield up to 40%, easy industrial production, low relative cost and simple operation steps.

Description

Preparation method of Boc-D-isoleucine
Technical Field
The invention relates to a preparation method of Boc-D-isoleucine, belonging to the technical field of medical intermediates.
Background
Boc-D-isoleucine, english name Boc-D-isoleucine, CAS 55721-65-8, is non-natural chiral small molecular amino acid, and is a synthetic raw material for various novel small peptide drugs, macrocyclic antibiotics, anticancer drugs (HTLV-1 reverse transcription inhibitors), pepsin-resistant intestinal stabilizing peptide lead frames, gram negative active cationic lipopeptide antibiotics, antibacterial peptides and the like.
For the Boc-D-isoleucine synthesis method, the related literature is not plentiful, but as the demand of the medical market is gradually increased, the corresponding synthesis method needs to be developed to meet the daily-growth market demand. At present, the synthetic routes of Boc-D-isoleucine and related intermediates all have limitations, and the main synthetic methods are as follows:
synthetic route 1: natural L-isoleucine is adopted as a starting material, racemized by acetic anhydride after acetylation, and selectively hydrolyzed by acetyl hydrolase to obtain a target product; the reaction equation is as follows:
however, the actual main products of the reaction are D-allo-isoleucine and a small amount of D-isoleucine target products, the subsequent separation treatment cost is extremely high, and the reaction is not suitable for large-scale production.
Synthetic route 2: the special fatty methylase synthesized by self is adopted, so that the synthesis difficulty is high, the cost is high, and the reference is not provided; the reaction equation is as follows:
synthetic route 3: the target product is obtained through the steps of selective hydrogenation, lactone ring opening, transiodination, hydrogenation, deacetylation, ester hydrolysis and the like. The starting materials of the route are not commercially available, the synthesis is troublesome, the route is longer, and the comprehensive yield is not high; the reaction equation is as follows:
in summary, the synthetic route has the disadvantages of more or less difficult synthesis, difficult raw materials, difficult separation, low productivity, and the like, so that it is necessary to develop a novel chemical preparation route to meet the increasing demand of the amino acid.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention aims to provide a preparation method of (2R, 3R) -2-amino-3-methylbutanoic acid, which takes phenyloxazolidone and bromoacetate as raw materials and generates a compound A by amination under the action of strong alkali; then esterifying the mixture with crotyl alcohol to generate a compound B; then dehydrogenating under the action of a lithium reagent, generating a claisen rearrangement to generate a compound C, dissociating trimethylchlorosilane to obtain a compound D, and hydrolyzing hydrochloric acid to obtain a compound E; finally, the catalytic hydrogenation addition and Boc protection are carried out simultaneously to obtain Boc-D-isoleucine. Boc-D-isoleucine is convenient for storage and can be directly deprotected to obtain the product. The preparation method has the advantages of easily obtained raw materials, high total yield up to 40%, easy industrial production, low relative cost and simple operation steps.
To achieve the above object, the process for preparing (2R, 3R) -2 amino-3-methylbutyric acid according to the present invention comprises the steps of:
step one: phenyl oxazolidinone reacts with bromoacetate in the presence of cesium carbonate in an organic solvent, and then hydrolyzes under alkaline conditions to give (R) -2- (2-oxo-4-phenyloxazolidin-3-yl) acetic acid (compound A); the reaction equation is expressed as follows:
step two: the compound A reacts with acyl chloride and then is esterified with crotyl alcohol to obtain (E) -but-2-en-1-yl (R) -2- (2-oxo-4-phenyl oxazolidin-3-yl) acetate (compound B); the reaction equation is expressed as follows:
step three: under the action of LiHMDS and cuprous iodide, the compound B undergoes claisen rearrangement to obtain an intermediate transition state C, then is treated by trimethylchlorosilane, is subjected to acid-base washing to obtain a compound D, and is hydrolyzed with a hydrochloric acid solution in acetone to obtain (2R, 3R) -2-amino-3-methylpent-4-enacid hydrochloride (compound E); the reaction equation is expressed as follows:
step four: mixing the compound E with methyl tertiary butyl ether, adding triethylamine for dissociation, filtering, concentrating the filtrate under reduced pressure, dissolving in an alcohol solvent, adding palladium-carbon and di-tertiary butyl dicarbonate, and introducing hydrogen for reaction under 15-30Psi to obtain Boc-D-isoleucine (compound F). The reaction equation is expressed as follows:
further, in the above technical scheme, in the step one, the bromoacetate is selected from methyl bromoacetate or ethyl bromoacetate.
Further, in the above technical scheme, in the step one, the organic solvent is selected from N, N-dimethylformamide or dimethyl sulfoxide.
Further, in the above technical scheme, the molar ratio of phenyl oxazolidinone, cesium carbonate and bromoacetate is 1:1.35-1.40:2.40-2.60.
Further, in the above technical scheme, in the second step, the acyl chloride is selected from thionyl chloride or oxalyl chloride, and the organic solvent is selected from toluene or n-heptane. Under the preferred condition, the acyl chloride is thionyl chloride, the organic solvent is n-heptane, and a small amount of DMF is added for catalysis, and the acyl chloride temperature and the acyl chloride time are 65-70 ℃/5-6 hours respectively.
Further, in the above technical scheme, in the second step, the molar ratio of the compound a, the acid chloride to the crotyl alcohol is 1:1.15-1.20:1.15.
further, in the above technical scheme, in the third step, the molar ratio of the compound B, cuprous iodide, liHMDS, trimethylchlorosilane to hydrochloric acid is 1:1.05-1.10:1.40-1.50:1.40-1.50:2.0-2.5.
Further describing the embodiment of the invention, in the third step, in order to avoid the application of a large amount of acid-base purification, a continuous reaction mode is adopted, and finally, the purification is performed at one time in a hydrochloric acid hydrolysis step.
Further, in the above technical scheme, in the fourth step, the molar ratio of the compound E, triethylamine to di-tert-butyl dicarbonate is 1:1.2-1.25:1.2-1.30.
Further illustrating the embodiments of the present invention, the fourth step results in less catalytic hydrogenation addition and Boc protection impurities (micro double Boc protection), and the reaction can be carried out at normal pressure by pressurizing 15-30Psi, but at least 2-3 substitutions are needed due to carbon dioxide generated during Boc protection.
Advantageous effects of the invention
The raw materials used in the chemical synthesis reaction related by the invention are cheap, the reaction steps are fewer in the whole experimental operation process, the operation safety is higher, the yield is high, the purity of the product is high, the method has very wide application prospect and market value in the field of medicine, and the total yield of the final reaction of the synthesis process is about 40 percent calculated by the phenyl oxazolidone.
Drawings
FIG. 1 is a HNMR spectrum of the Boc-D-isoleucine product obtained in example 6.
Detailed Description
Example 1
(4R) -phenyl-2-oxazolidinone (100 g,0.612 mol) was dissolved in DMSO (700 mL), stirred well, cooled to 0deg.C, cesium carbonate (279.5 g,0.858 mol) was added, stirred for 10 minutes, then methyl bromoacetate (234.4 g, 1.552 mol) was added, and stirred at room temperature for 2 hours. Then MTBE (1000 mL) and 1N hydrochloric acid are added for quenching (the temperature is controlled at 15-20 ℃), standing and layering are carried out, the organic phase is saturated with saline, the organic phase is 3N sodium hydroxide for regulating pH to be 12-13, standing and layering are carried out, the aqueous phase is 1N hydrochloric acid for regulating pH to be 2-3, EA extraction is carried out 300mL multiplied by 3 times, spin drying is combined, N-heptane is added for pulping and crystallizing, 116.6g of off-white solid A is obtained, and the yield is 84% and HPLC is 97.9%. 1 H-NMR(400MHz,CDCl3)δ:12.89(s,1H),7.47-7.39(m,3H),7.35-7.29(m,2H),5.09-5.03(m,1H),4.76-4.70(m,1H),4.35-4.31(m,1H),4.21-4.16(m,1H),3.46-3.42(m,1H)。
Example 2
(4R) -phenyl-2-oxazolidinone (100 g,0.612 mol) was dissolved in DMF (1000 mL), stirred well, cooled to 0deg.C, cesium carbonate (279.5 g,0.858 mol) was added, stirred for 10 minutes, ethyl bromoacetate (417.5 g, 1.552 mol) was added, and stirred at room temperature for 5 hours. Then MTBE (1000 mL) and 1N hydrochloric acid are added for quenching (the temperature is controlled at 15-20 ℃), standing and layering are carried out, an organic phase is washed by water, the pH value of the organic phase is regulated to be 12-13 by 3N sodium hydroxide, standing and layering are carried out, the pH value of an aqueous phase is regulated to be 2-3 by 1N hydrochloric acid, EA is used for extracting 300mL multiplied by 3 times, spin drying is combined, N-heptane is added for pulping and crystallizing, 103g of off-white solid A is obtained, and the yield is 76% and HPLC is 96.5%.
Example 3
After compound A (99.5 g,0.45 mol) and DMF (0.2 g) were dissolved in N-heptane (600 mL), thionyl chloride (64.2 g,0.54 mol) was added dropwise at a temperature below 40℃and allowed to react for 8 hours at 65-70℃and allowed to stand, a small amount of brown solution in the lower layer was separated, the upper layer was dried by spinning, 500mL of N-heptane was added and continued to be dried by spinning, the temperature was lowered to room temperature, dichloromethane (600 mL) and crotyl alcohol (38.9 g,0.54 mol) were added, triethylamine (62.38 g,0.63 mol) were added dropwise at low temperature, after stirring at room temperature for 2 hours, 1N hydrochloric acid was quenched, aqueous potassium bicarbonate solution and water were washed, isopropyl acetate and N-heptane were added and recrystallized to give 108.5g of white solid B, yield 87.6% and HPLC99.3%. 1 H-NMR(400MHz,CDCl3)δ:7.48-7.36(m,3H),7.35-7.28(m,2H),5.67-5.61(m,2H),5.12-5.04(m,1H),4.76-4.69(m,1H),4.30-4.26(m,1H),4.241-4.11(m,3H),3.38-3.34(m,1H),1.28-1.24(m,3H).
Example 4
After compound A (99.5 g,0.45 mol) and DMF (0.2 g) were dissolved in toluene (540 mL), thionyl chloride (64.2 g,0.54 mol) was added dropwise at a temperature below 40℃and reacted for 5 hours at 60-75℃and dried by spinning 500mL of toluene was added and cooled to room temperature, methylene chloride (600 mL) and crotyl alcohol (38.9 g,0.54 mol) were added, triethylamine (62.38 g,0.63 mol) was added dropwise at a low temperature, after stirring at room temperature for 2 hours, 1N hydrochloric acid was quenched, aqueous potassium bicarbonate and water were washed, dried by spinning, isopropyl acetate and N-heptane were added to recrystallize to give 106.7g of yellow solid B in a yield of 86.1% and HPLC of 97.7%.
Example 5
Compound B (106 g,0.385 mol) was dissolved in THF (1000 mL), cooled to-78 ℃, and then mixed solution of cuprous iodide dimethyl sulfide (102.1 g,0.404 mol) and THF (200 mL) was added dropwise, after 30 minutes, liHMDS (578 mL,0.578 mol) was added dropwise at this temperature, the temperature was allowed to react for 2 hours, slowly warmed to-20 ℃, stirred overnight, then heated to 40 ℃ for 2 hours, cooled down, quenched with trimethylchlorosilane (62.7 g,0.578 mol), ph=4.5-5.0 with 10% aqueous citric acid, allowed to stand for delamination, dried by spin, aqueous MTBE extracted, washed with saturated brine after combining, dried by spin, added with 30% hydrochloric acid 118g, warmed up to 85 ℃ for reaction for 7 hours, dried by spin to moisture < 0.15% acetone (600 mL), warmed up to pulp, filtered to obtain 45.1g of compound E, 70.7% of UPLC, and cooled down to yield 96.3%. 1 H-NMR(400MHz,CD3OD)δ:5.77-5.71(m,1H),5.20-5.14(m,2H),3.54-3.50(m,1H),2.76-2.72(m,1H),1.18-1.12(m,3H).
Example 6
Compound E (41.4 g,0.25 mol) was dissolved in MTBE (500 mL), cooled to 0-5℃and triethylamine (30.4 g,0.3 mol) was added dropwise, stirred for 3 hours after the addition was completed, filtered, the filter cake was rinsed with MTBE, the filtrate was dried by spinning, ethanol (200 mL), boc anhydride (65.5 g,0.3 mol) and 10% Pd were addedAfter replacing the catalyst with hydrogen for three times, pressurizing to 15-30psi, maintaining the pressure at 20-25 ℃ for reaction overnight, filtering after releasing pressure the next day, leaching palladium-charcoal with ethanol, spin-drying, pulping and crystallizing to obtain 52.5g of product white powder Boc-D-isoleucine, the yield is 90.8%, UPLC is 99.6%, and the ee is 98%. 1 H-NMR(400MHz,DMSO-d 6 )δ:12.46(s,1H),6.97(d,1H),3.86-3.82(m,1H),1.76-1.71(m,1H),1.40-1.37(m,10H),1.25-1.15(m,1H),0.87-0.82(m,6H).
The foregoing describes specific embodiments of the present invention. It is to be understood that the invention is not limited to the particular embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the claims without affecting the spirit of the invention.

Claims (8)

1. The preparation method of Boc-D-isoleucine is characterized by comprising the following steps:
step one: phenyl oxazolidinone reacts with bromoacetate in the presence of cesium carbonate in an organic solvent, and then hydrolyzes under alkaline conditions to give (R) -2- (2-oxo-4-phenyloxazolidin-3-yl) acetic acid (compound A);
step two: the compound A reacts with acyl chloride and then is esterified with crotyl alcohol to obtain (E) -but-2-en-1-yl (R) -2- (2-oxo-4-phenyl oxazolidin-3-yl) acetate (compound B);
step three: under the action of LiHMDS and cuprous iodide, the compound B undergoes claisen rearrangement to obtain an intermediate transition state C, then is treated by trimethylchlorosilane, is subjected to acid-base washing to obtain a compound D, and is hydrolyzed with a hydrochloric acid solution in acetone to obtain (2R, 3R) -2-amino-3-methylpent-4-enacid hydrochloride (compound E);
step four: mixing the compound E with methyl tertiary butyl ether, adding triethylamine for dissociation, filtering, concentrating the filtrate under reduced pressure, dissolving in an alcohol solvent, adding palladium-carbon and di-tertiary butyl dicarbonate, and introducing hydrogen for reaction under 15-30Psi to obtain Boc-D-isoleucine (compound F).
2. The method for producing Boc-D-isoleucine according to claim 1, wherein: in the first step, the bromoacetate is selected from methyl bromoacetate or ethyl bromoacetate.
3. The method for producing Boc-D-isoleucine according to claim 1, wherein: in the first step, the organic solvent is selected from N, N-dimethylformamide or dimethyl sulfoxide.
4. The method for producing Boc-D-isoleucine according to claim 1, wherein: in the first step, the molar ratio of the phenyl oxazolidone, the cesium carbonate and the bromoacetate is 1:
1.35-1.40：2.40-2.60。
5. the method for producing Boc-D-isoleucine according to claim 1, wherein: in the second step, the acyl chloride is selected from thionyl chloride or oxalyl chloride, and the organic solvent is selected from toluene or n-heptane.
6. The method for producing Boc-D-isoleucine according to claim 1, wherein: in the second step, the molar ratio of the compound A, the acyl chloride and the crotyl alcohol is 1:1.15-1.20:1.15.
7. the method for producing Boc-D-isoleucine according to claim 1, wherein: in the third step, the molar ratio of the compound B, the cuprous iodide, the LiHMDS, the trimethylchlorosilane and the hydrochloric acid is 1:1.05-1.10:1.40-1.50:1.40-1.50:2.0-2.5.
8. The method for producing Boc-D-isoleucine according to claim 1, wherein: in the fourth step, the molar ratio of the compound E, triethylamine and di-tert-butyl dicarbonate is 1:1.2-1.25:1.2-1.30.
CN202311355939.5A 2023-10-19 2023-10-19 Preparation method of Boc-D-isoleucine Pending CN117417272A (en)

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RU2233839C1 (en) * 2000-07-13 2004-08-10 Санкио Компани, Лимитед Derivatives of aminoalcohols, pharmaceutical composition, method for prophylaxis or treatment, intermediate compounds and method for preparing intermediate compounds
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