CN111205251B - Preparation method of chiral ligand (3S,4S) -2, 5-dioxy tetrahydrofuran-3, 4-bis-carbamic acid benzyl ester - Google Patents
Preparation method of chiral ligand (3S,4S) -2, 5-dioxy tetrahydrofuran-3, 4-bis-carbamic acid benzyl ester Download PDFInfo
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Abstract
The invention relates to the field of chiral transition metal catalysts, in particular to a preparation method of chiral transition metal catalyst intermediate (3S,4S) -2, 5-dioxytetrahydrofuran-3, 4-bis-benzyl carbamate, which uses racemic-2, 3-dibromo-succinic acid as a raw material to generate diester (I) through esterification reaction under the catalysis of acid, the compound (I) and amine are subjected to nucleophilic substitution reaction to obtain compound (II), the compound (II) is subjected to removal reaction under the action of trifluoroacetic acid to obtain amino diester (III), the compound (III) and acyl chloride are subjected to acylation reaction to obtain amide (IV), ester group of the compound (IV) is hydrolyzed into acid (V) under alkaline condition, and finally the compound (V) is dehydrated in molecule to obtain the chiral transition metal catalyst intermediate. The reaction operation is simple, the use of expensive palladium reagent is avoided, and the cost is low.
Description
Technical Field
The invention belongs to the field of chiral transition metal catalysts, and particularly relates to a preparation method of (3S,4S) -2, 5-dioxytetrahydrofuran-3, 4-bis-benzyl carbamate.
Background
The oxidation reaction of olefin, especially the stereoselective oxidation, is an important organic reaction and has wide application in organic synthesis; sulfides can be oxidized into chiral sulfoxides, and optically active sulfoxides, such as methyl p-toluene sulfone, are common substrates for synthesizing a plurality of natural products, and the stereoselective oxidation reactions of olefins and sulfides require chiral transition metal catalyst ligands, wherein (3S,4S) -2, 5-dioxytetrahydrofuran-3, 4-bis-carbamic acid benzyl ester is used as an important ligand of the chiral transition metal catalyst.
The development work of the synthesis process is worth researching by chemical workers.
Refer to the synthetic methods of the compounds, wherein the Journal of the Chinese Chemical Society; vol.42; nb.5; (1995) (ii) a p.847-860 reports:
in the literature, racemic-2, 3-dibromosuccinic acid is used as an initial raw material, and is subjected to nucleophilic substitution reaction to generate 2, 3-dibenzylamine 1, 4-succinic acid, then the benzyl of the raw material is removed by palladium-carbon to obtain 2, 3-diamino-1, 4-succinic acid, amino acid is subjected to acylation reaction to obtain amide, and finally, two molecules of acid are subjected to intramolecular dehydration to obtain anhydride.
The disadvantages of this route are: the intermediate benzylamine acid and amino acid have poor solubility in various solvents, are not easy to extract in the reaction process and participate in the next reaction, acetic acid-hydrochloric acid is used as a solvent in the benzylamine acid deprotection reaction, an expensive palladium reagent is required, the cost is high, and the industrialization is not facilitated.
In order to solve the problems in the existing literature, a simpler and more convenient synthesis method is sought, and the production cost is reduced, the synthesis steps of the compound are further researched, and a route suitable for industrial production is found, so that the method is more beneficial to large-scale production.
Disclosure of Invention
The purpose is as follows: in order to overcome the defects in the prior art, the invention provides a preparation method of (3S,4S) -2, 5-dioxytetrahydrofuran-3, 4-benzyl dicarbamate, wherein racemic-2, 3-dibromosuccinic acid is used as a raw material, firstly, a compound (I) is generated through an esterification reaction under the catalysis of acid, a compound (II) is obtained through a nucleophilic substitution reaction of the compound (I) and amine, a removal reaction of the compound (II) is performed under the action of trifluoroacetic acid to obtain a compound (III), the compound (III) and acyl chloride are subjected to an acylation reaction to obtain amide (IV), the compound (IV) is hydrolyzed to obtain a compound (V), and finally, the compound (V) is subjected to intramolecular dehydration to obtain anhydride (VI).
The invention provides a new preparation method for (3S,4S) -2, 5-dioxytetrahydrofuran-3, 4-bis-benzyl carbamate, has simple reaction operation, mild conditions, lower cost and higher yield, and can realize stable industrial production and preparation.
The technical scheme is as follows: in order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a compound which is a chiral transition metal catalyst intermediate, said compound being benzyl (3S,4S) -2, 5-dioxotetrahydrofuran-3, 4-biscarbamate having the chemical formula:
a method for preparing benzyl (3S,4S) -2, 5-dioxytetrahydrofuran-3, 4-dicarbamate comprises the following steps: using racemic-2, 3-dibromo-succinic acid as a raw material, firstly, generating a compound (I) through an esterification reaction under the catalysis of acid, obtaining a compound (II) through a nucleophilic substitution reaction of the compound (I) and amine, performing a removal reaction of the compound (II) under the action of trifluoroacetic acid to obtain a compound (III), performing an acylation reaction of the compound (III) and acyl chloride to obtain amide (IV), hydrolyzing the compound (IV) to obtain a compound (V), and finally performing intramolecular dehydration on the compound (V) to obtain anhydride (VI).
The synthetic route is as follows:
wherein R is methyl, ethyl, tert-butyl, etc.
Further, the method specifically comprises the following steps:
step 1) using racemized-2, 3-dibromo succinic acid as a raw material to obtain a compound I through an esterification reaction with alcohol under an acidic condition;
step 2), carrying out nucleophilic substitution reaction on the compound I and alkylamine under the action of alkali to obtain a compound II;
step 3), carrying out a removal reaction on the compound II under the action of trifluoroacetic acid to obtain a compound III;
step 4), carrying out acylation reaction on the compound III and acyl chloride under an alkaline condition to obtain a compound IV;
step 5), hydrolyzing the compound IV under an alkaline condition to obtain a compound V;
and 6) carrying out intramolecular dehydration on the compound V to obtain VI, namely (3S,4S) -2, 5-dioxytetrahydrofuran-3, 4-bis-benzyl carbamate.
Further, in the step 1), the acid is one of hydrogen chloride, sulfuric acid and thionyl chloride. The reaction temperature is 25 ℃, and the reaction time is 1-2 h.
Further, in the step 2), the reaction solvent is one or more of DCM, DMF and ethanol; the alkali is one or more of triethylamine, sodium hydroxide, sodium bicarbonate and potassium hydroxide; the reaction temperature is 20-25 ℃, and the reaction time is 3-5 h.
Further, in the step 3), the reaction temperature is 50-80 ℃, and the reaction time is 1-2 h.
Further, in the step 4), the base is one or more of triethylamine, sodium hydroxide and sodium bicarbonate; the solvent is one or more of THF, DCM and acetone; the reaction temperature is 0-20 ℃, and the reaction time is 1-2 h.
Further, in the step 5), the reaction solvent is one or more of water, methanol and ethanol; the alkali is one of sodium hydroxide and potassium hydroxide; the reaction temperature is 25-35 ℃, and the reaction time is 1-3 h.
Further, in the step 6), the dehydrating reagent is acetic anhydride, the reaction temperature is 80-100 ℃, and the reaction time is 1-3 h.
The invention has the beneficial effects that: the preparation method of (3S,4S) -2, 5-dioxytetrahydrofuran-3, 4-bis-benzyl carbamate provided by the invention is simple to operate, low in cost and beneficial to industrial production, and is particularly shown in the following aspects: the method has the advantages of simple and convenient reaction, mild reaction conditions, high reaction yield and low cost, the problem of poor solubility of amino acids in the literature is solved by converting the acid into the ester in the first step, the operation is simple and convenient, the yield is improved, side reactions are avoided, p-methoxybenzylamine is used for replacing benzylamine, palladium carbon is avoided when the next step of amino deprotection is carried out, the cost is reduced, the operation is simplified, and the method has important significance for researching and developing a preparation method of (3S,4S) -2, 5-dioxytetrahydrofuran-3, 4-bis-carbamic acid benzyl ester and amplifying production.
Detailed Description
The present invention will be further described with reference to the following examples.
Abbreviation comparison table
| DCM | Methylene dichloride |
| 1H-NMR | Hydrogen spectrum of nuclear magnetic resonance |
| TLC | Thin layer chromatography |
| CDCl3 | Chloroform |
| THF | Tetrahydrofuran (THF) |
| Acetone | Acetone (II) |
A compound which is benzyl (3S,4S) -2, 5-dioxotetrahydrofuran-3, 4-biscarbamate having the following chemical formula:
the preparation method comprises the following steps: using racemic-2, 3-dibromo-succinic acid as a raw material, firstly, generating a compound (I) through an esterification reaction under the catalysis of acid, obtaining a compound (II) through a nucleophilic substitution reaction of the compound (I) and amine, performing a removal reaction of the compound (II) under the action of trifluoroacetic acid to obtain a compound (III), performing an acylation reaction of the compound (III) and acyl chloride to obtain amide (IV), hydrolyzing the compound (IV) to obtain a compound (V), and finally performing intramolecular dehydration on the compound (V) to obtain anhydride (VI).
The synthetic route is as follows:
wherein R is methyl, ethyl, tert-butyl, etc.
The first embodiment is as follows:
meso-2, 3-dibromo-succinic acid (27.5g,1eq) and methanol (250mL) were added to a reaction flask, and then thionyl chloride (23.6g,2.5eq) was slowly added dropwise, after completion of the addition, the mixture was reacted at room temperature for 2 hours, and concentrated under reduced pressure to obtain compound I, meso-2, 3-dibromo-succinic acid methyl ester (29.7 g, yield 98%).1H-NMR(CDCl3)δ4.69(s,2H),3.86(s,6H)。
Example two:
p-methoxybenzylamine (20g,1.5eq) was added to a solution of compound i (29.6g,1eq) in DCM (200mL), triethylamine (19.6g,2eq) was added under ice water cooling, stirring was carried out at room temperature for 3 hours, after completion of the reaction, water (100g) was added and extraction was carried out, DCM (200mL) was added, the organic phases were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 38.5g of compound ii (yield 95%).1H-NMR(CDCl3)δ4.21(d,2H),3.66(s,6H),3.83(m,6H),2.20(s,2H),,1.71(d,4H),6.59-6.88(m,8H)。
Example three:
compound ii (38.5g,1eq), trifluoroacetic acid (26.4g,2.5eq) were added to a reaction flask, heated to 80 ℃ and reacted for 2h, the LC starting material disappeared, cooled to room temperature, concentrated, slurried with ethyl acetate and n-hexane, filtered, the filtrate was adjusted to pH 10 with 2M sodium hydroxide solution, a solid precipitated, filtered, and the solid was dried under vacuum to give 15.6g of compound iii (96% yield).1H-NMR(CDCl3)δ3.83(s,6H),2.10(s,2H),4.86(m,4H)。
Example four:
compound iii (15.5g,1eq), triethylamine (20g,2.2eq) and THF (150mL) were charged to a reaction flask, benzyl chloroformate (1.5eq) was added dropwise at 0 ℃, reacted at 20 ℃ for 5h after completion of the addition, cooled, added 100g of water, extracted twice with 100mL of diethyl ether, the aqueous phase was adjusted to pH 2-3 with hydrochloric acid, left overnight, filtered and the solid was dried under vacuum to give 40g of compound iv (yield 93%).1H-NMR(CDCl3)δ7.35(s,10H),5.84(d,2H),5.13(s,4H),4.95(d,2H),3.75(s,6H)。
Example five:
compound iv (40g) was dissolved in methanol (100mL), sodium hydroxide (8g,2.2eq), 10g water were added to the reaction flask, the temperature was raised to 35 ℃ and stirred for 1h, TLC starting material disappeared, DCM (200mL) was extracted, the aqueous phase was adjusted to pH 2-3 with hydrochloric acid, left overnight, filtered, and the solid was dried in vacuo to give 37g of compound v. (yield 99%).1H-NMR(CDCl3)δ5.69(s,4H),5.41(d,2H),7.38-7.47(m,10H),5.03(d,2H),2.6(s,2H)。
Example six:
compound V (37g) and acetic anhydride (300mL) were added to a reaction flask, reacted at 80 ℃ for 1 hour, cooled, and concentrated to give a crude product, which was added to chloroform and stirred, filtered, and n-hexane was added to the filtrate to crystallize 32g of benzyl (3S,4S) -2, 5-dioxotetrahydrofuran-3, 4-biscarbamate (yield 90%).1H-NMR(Acetone)δ5.09(d,2H),5.70(s,4H),7.35-7.47(m,10H),8.08(d,2H)。
The above description is only of the preferred embodiments of the present invention, and it should be noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the invention and these are intended to be within the scope of the invention.
Claims (9)
- A process for the preparation of benzyl (3S,4S) -2, 5-dioxatetrahydrofuran-3, 4-biscarbamate, wherein the benzyl (3S,4S) -2, 5-dioxatetrahydrofuran-3, 4-biscarbamate has the following chemical formula:
the preparation method comprises the following steps: using racemic-2, 3-dibromo-succinic acid as a raw material, firstly, carrying out esterification reaction under the catalysis of acid to generate a compound I, carrying out nucleophilic substitution reaction on the compound I and amine to obtain a compound II, carrying out removal reaction on the compound II under the action of trifluoroacetic acid to obtain a compound III, carrying out acylation reaction on the compound III and acyl chloride to obtain a compound IV, hydrolyzing an ester group of the compound IV under an alkaline condition to obtain a compound V-, and finally, carrying out intramolecular dehydration on the compound V to obtain a compound VI (3S,4S) -2, 5-dioxytetrahydrofuran-3, 4-benzyl biscarbamate;the synthetic route is as follows:
wherein R is methyl, ethyl or tert-butyl. - 2. The process for the preparation of benzyl (3S,4S) -2, 5-dioxatetrahydrofuran-3, 4-biscarbamate according to claim 1, comprising the steps of:step 1) using racemized-2, 3-dibromo succinic acid as a raw material to obtain a compound I through an esterification reaction with alcohol under an acidic condition;step 2), carrying out nucleophilic substitution reaction on the compound I and alkylamine under the action of alkali to obtain a compound II;step 3), carrying out a removal reaction on the compound II under the action of trifluoroacetic acid to obtain a compound III;step 4), carrying out acylation reaction on the compound III and acyl chloride under an alkaline condition to obtain a compound IV;step 5), hydrolyzing the compound IV under an alkaline condition to obtain a compound V;and 6) carrying out intramolecular dehydration on the compound V to obtain a compound VI, namely (3S,4S) -2, 5-dioxytetrahydrofuran-3, 4-bis-benzyl carbamate.
- 3. Process for the preparation of benzyl (3S,4S) -2, 5-dioxatetrahydrofuran-3, 4-biscarbamate according to claim 2, characterized in that: in the step 1), the acid is one of hydrogen chloride, sulfuric acid and thionyl chloride.
- 4. Process for the preparation of benzyl (3S,4S) -2, 5-dioxatetrahydrofuran-3, 4-biscarbamate according to claim 2, characterized in that: in the step 1), the reaction temperature is 25 ℃, and the reaction time is 1-2 h.
- 5. Process for the preparation of benzyl (3S,4S) -2, 5-dioxatetrahydrofuran-3, 4-biscarbamate according to claim 2, characterized in that: in the step 2), the reaction solvent is one or more of DCM, DMF and ethanol; the alkali is one or more of triethylamine, sodium hydroxide, sodium bicarbonate and potassium hydroxide; the reaction temperature is 20-25 ℃, and the reaction time is 3-5 h.
- 6. Process for the preparation of benzyl (3S,4S) -2, 5-dioxatetrahydrofuran-3, 4-biscarbamate according to claim 2, characterized in that: in the step 3), the reaction temperature is 50-80 ℃, and the reaction time is 1-2 h.
- 7. Process for the preparation of benzyl (3S,4S) -2, 5-dioxatetrahydrofuran-3, 4-biscarbamate according to claim 2, characterized in that: in the step 4), the alkali is one or more of triethylamine, sodium hydroxide and sodium bicarbonate; the solvent is one or more of THF, DCM and acetone; the reaction temperature is 0-20 ℃, and the reaction time is 1-2 h.
- 8. Process for the preparation of benzyl (3S,4S) -2, 5-dioxatetrahydrofuran-3, 4-biscarbamate according to claim 2, characterized in that: in the step 5), the reaction solvent is one or more of water, methanol and ethanol; the alkali is one of sodium hydroxide, potassium hydroxide and lithium hydroxide; the reaction temperature is 25-35 ℃, and the reaction time is 1-3 h.
- 9. Process for the preparation of benzyl (3S,4S) -2, 5-dioxatetrahydrofuran-3, 4-biscarbamate according to claim 2, characterized in that: in the step 6), the dehydration reagent is acetic anhydride, the reaction temperature is 80-100 ℃, and the reaction time is 1-3 h.
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| WO2020006722A1 (en) * | 2018-07-05 | 2020-01-09 | Hangzhou Dac Biotech Co., Ltd | Cross-linked pyrrolobenzodiazepine dimer (pbd) derivative and its conjugates |
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| CN107501112A (en) * | 2017-09-15 | 2017-12-22 | 苏州爱玛特生物科技有限公司 | A kind of Chiral Synthesis of chiral beta amino acids and the synthetic method of medicine intermediate |
| CN108727242A (en) * | 2018-05-31 | 2018-11-02 | 常州制药厂有限公司 | A kind of preparation method of the trans- -4- cyclohexyl-L-PROLINE of blood-pressure drug key intermediate |
| WO2020006722A1 (en) * | 2018-07-05 | 2020-01-09 | Hangzhou Dac Biotech Co., Ltd | Cross-linked pyrrolobenzodiazepine dimer (pbd) derivative and its conjugates |
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