CN114436929A - Synthesis method of N-protected 3, 4-dehydro-L-proline ester - Google Patents

Synthesis method of N-protected 3, 4-dehydro-L-proline ester Download PDF

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CN114436929A
CN114436929A CN202111674981.4A CN202111674981A CN114436929A CN 114436929 A CN114436929 A CN 114436929A CN 202111674981 A CN202111674981 A CN 202111674981A CN 114436929 A CN114436929 A CN 114436929A
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高寻
杨学军
刘国胜
陈达
王雷
许智
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Duchuang Chongqing Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C—CHEMISTRY; METALLURGY
    • 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

Abstract

The invention provides a method for synthesizing N-protected 3, 4-dehydro-L-proline ester, which adopts N-protected L-hydroxyproline which is sufficient in market supply and easy to obtain as a raw material in a synthetic route, and obtains a product through three steps of reaction. The method has the advantages of easily obtained raw materials, simple and convenient operation, high overall yield, controllable three wastes, environmental protection and easy industrial production. The invention has important social value and economic value, and simultaneously provides guarantee for the production of downstream products and the industrial production and cost control of related medicines.

Description

Synthesis method of N-protected 3, 4-dehydro-L-proline ester
Technical Field
The invention relates to the field of organic synthesis, in particular to a synthetic method of a medical intermediate, and specifically relates to a synthetic method of N-protected 3, 4-dehydro-L-proline ester.
Background
The N-protected-3, 4-dehydro-L-proline ester is an important medical synthetic intermediate and is used for constructing parent nucleus structures of various medicaments. For example, the oral drug PAXLOVID of pfeiffer, the compound N-protected 3, 4-dehydro-L-proline ester is a key drug molecule from retrosynthetic analysis and literature searchA bond intermediate. Among them, N-BOC-3, 4-dehydro-L-proline methyl ester of formula C is most commonly used11H17NO4Molecular weight 227.26, CAS number 74844-93-2. Therefore, the industrialized research of the synthesis process of the N-protected 3, 4-dehydro-L-proline ester has very important social benefits and wide market prospect and economic value.
Figure BDA0003450842260000011
The prior art has more records about the synthesis of the compounds, but the industrialization is still difficult at present, the technical difficulty is that the compounds contain a chiral center and an unsaturated five-membered ring structure, so the reaction conditions are required to be mild so as to prevent racemization, oxidation or ring opening; in addition, as an intermediate, the method is sensitive to production cost, and the cost of raw materials and the cost of separation and purification are all reduced as much as possible.
The literature reports that the synthesis scheme of N-Boc-3, 4-dehydro-L-proline ester has two main types:
scheme 1:
Figure BDA0003450842260000021
the drawbacks of route 1 are mainly: in the first step, a highly toxic product MsCl is used, and the advantages of industrial production are not provided; in the elimination step, in order to eliminate mild conditions and ensure chiral purity, an organic selenium reagent is adopted, but the reagent is expensive; and in the third step, the oxidation condition of hydrogen peroxide is not easy to control. In addition, since the starting material is Boc protected proline methyl ester, the separation and purification in each step are difficult, and the separation is difficult without column chromatography, which is not favorable for industrial production.
Scheme 2:
Figure BDA0003450842260000022
scheme 2 introduces a double bond by olefin metathesis followed by selective hydrolysis by enzymatic resolution to give the carboxylic acid of the desired configuration, which can be finally methylated to give N-Boc-3, 4-dehydro-L-proline ester. The cost of the reagent of the route is high, and heavy metal is introduced in the olefin metathesis reaction; enzymatic resolution loses a portion of the material and yields are low, and therefore not suitable for the production of this compound.
Therefore, how to optimize the preparation and purification method of N-Boc-3, 4-dehydro-L-proline ester to achieve a process suitable for industrial scale-up is a technical problem to be solved at present.
Disclosure of Invention
In view of the shortage of the synthetic methods, the invention aims to provide a synthetic method of N-protected-3, 4-dehydro-L-proline ester, which is used for solving the problems in the prior art.
The invention provides a synthetic method of N-protection-3, 4-dehydrogenation-L-proline ester, which has the following reaction formula:
Figure BDA0003450842260000031
the method comprises the following steps: using a compound shown in a formula I as a starting material, and reacting to obtain an intermediate compound shown in a formula II;
step two: carrying out leaving reaction on the intermediate compound shown in the formula II under alkaline conditions to generate an intermediate compound shown in the formula III;
step three: reacting the intermediate compound shown in the formula III into ester to obtain a compound shown in the formula IV, namely N-protected 3, 4-dehydro-L-proline ester;
R1selected from amino protecting groups; the amino protecting group is selected from Boc, Cbz, Bn, Bz, Fmoc, Alloc, Teoc, Ts, Tfa, Trt, Dmb, PMB or Pht. Boc is preferred.
R2Is a leaving group selected from fluorine, chlorine, bromine, iodine, or a substituted sulfonyl group selected from C1-6Alkyl-substituted sulfonyl, phenylsulfonyl, the phenyl ring of which may be substituted by 1 to 3C1-4Alkyl, alkoxy, halogen and nitro. Preferably selected from methylsulfonyl, ethylsulfonylPropylsulfonyl, butylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-methoxybenzenesulfonyl, 2-chlorobenzenesulfonyl, 2-fluorobenzenesulfonyl, 2, 6-dichlorobenzenesulfonyl, 2,4, 6-trichlorobenzenesulfonyl, 4-bromo-2-chlorobenzenesulfonyl, 2, 3-dichlorobenzenesulfonyl, 3-chlorobenzenesulfonyl, 3, 5-dichlorobenzenesulfonyl, 4-chlorobenzenesulfonyl, 2,4, 5-trichlorobenzenesulfonyl, 2, 4-dichlorobenzenesulfonyl, 3, 4-dichlorophenylmethylsulfonyl, 5-chloro-2, 4-difluorobenzenesulfonyl, 4-chloro-3-nitrobenzenesulfonyl, 3-bromobenzenesulfonyl, 2-bromobenzenesulfonyl, 4-bromobenzenesulfonyl, 4-bromo-3-fluorobenzenesulfonyl group, 4-bromo-2-fluorobenzenesulfonyl group, 4-nitrobenzenesulfonyl group, 2-nitrobenzenesulfonyl group, 3-nitrobenzenesulfonyl group, and more preferably p-methylbenzenesulfonyl group.
R3Is selected from C1-10Straight or branched chain hydrocarbon radical, C3-10Cycloalkyl radical, C6-10Aryl or heteroaryl, said C1-10The straight-chain or branched hydrocarbon radicals may be substituted by 1 to 3 halogen atoms or C3-6Cycloalkyl, phenyl, methylphenyl, dimethylphenyl, ethylphenyl, C3-10Cycloalkyl radical, C6-10The aryl or heteroaryl group may be substituted by 1 to 3C1-6Hydrocarbyl, halogen atom or nitro. Preference is given to methyl, ethyl, propyl, isopropyl, n-butyl, 2-sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, cyclohexyl, phenyl, benzyl, 4-methoxybenzyl, 4-nitrobenzyl, benzhydryl, trityl, 4-picolyl, beta-trichloroethyl, beta-methyl-thioethyl, beta-p-toluenesulfonylethyl, beta-p-nitrophenylthioethyl, trimethylsilyl, tert-butyldimethylsilyl, triethylsilyl, propargyl. Methyl and ethyl are particularly preferred.
The synthetic route of the invention uses N-protected L-hydroxyproline which is sufficiently available on the market as a raw material, and the compound of the formula I is easily purchased from the market or is easily prepared by carrying out corresponding amino protection reaction on the L-hydroxyproline based on the common general knowledge in the field.
The reaction reagent in the first step is: when R is2When selected from fluorine, the reagent is DAST, morphh-DAST, lithium fluorideSodium fluoride, potassium fluoride, tetrabutylammonium fluoride; when R2 is chlorine, the reagent is dichloromethane, chloroform, carbon tetrachloride, hexachloroethane, lithium chloride, sodium chloride, potassium chloride and tetrabutylammonium chloride; when R2 is selected from bromine, the reagent is methyl bromide, bromoform, tetrabromomethane, lithium bromide, sodium bromide, potassium bromide, tetrabutylammonium bromide and 1, 2-dibromo tetrafluoroethane, and when R2 is selected from iodine, the reagent is lithium iodide, sodium iodide, potassium iodide, tetrabutylammonium iodide, elementary iodine and methyl iodide. When R is2When it is a substituted sulfonyl group, it is R2-Cl、R2-Br or R2-O-R2Acid chlorides, acid bromides or acid anhydrides. The base used is selected from inorganic bases or organic bases according to the solvent, and is specifically selected from sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, cesium carbonate, cesium hydroxide, lithium carbonate, lithium hydroxide, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, diisopropylamine, dibutylamine, dicyclohexylamine, α -phenylethylamine, R-phenylethylamine, S-phenylethylamine, benzylamine, naphthylamine, 3-methylaminopropylamine, N '-dimethylethylenediamine, N N' -diethylethylenediamine, tetraethylenepentamine, cycleanine, triethylenetetramine, N-ethylethylenediamine, diethylenetriamine, and further preferably from sodium hydroxide or triethylamine; the equivalent of the base is 2.0 to 7.0 equivalents, and more preferably 3.6 equivalents.
Preferably, in the first step, water is used as a solvent, the temperature of the system is controlled to carry out reaction, and after the reaction is finished, an intermediate II is obtained by acidification, filtration and drying. The reaction temperature is-20 to 70 ℃, and the preferable temperature is 0 to 20 ℃.
As another preferred mode, an organic solvent can also be used in the first step, the compound in the formula I is firstly protected by pivaloyl chloride and then reacts with a reaction reagent, pivaloyl is hydrolyzed and removed in the post-treatment process, and the post-treatment of the reaction needs acidolysis and extraction.
And step two, the temperature of the system is controlled, the intermediate II is subjected to elimination reaction under the combined action of alkali and alcohol, carboxylic acid is formed after acidification, and the chiral purity e.e. value of the intermediate III can be kept above 99.0% through salifying and purifying with amine.
The base used in the elimination reaction in the step two is selected from one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide, DBU, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, butyl lithium, LDA and LiHMDS; sodium methoxide is more preferable.
In the second step, the reaction temperature is-20-60 ℃, more preferably 0-40 ℃, and still more preferably 10-30 ℃.
The alcohol used in the elimination reaction in the second step comprises methanol, ethanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isopentanol, tert-pentanol, 2- (methoxy) ethanol, 2- [2- (methoxy) ethoxy ] ethanol, 2- [2- (dimethylamino) -ethoxy ] ethanol, and is further optimized to be 2- [2- (dimethylamino) -ethoxy ] ethanol.
The solvent in the second step is selected from acetone, acetonitrile, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, 1, 3-dimethyl-2-imidazolidinone or a mixture thereof, and is more preferably acetonitrile.
The acid selected for acidification in the step two comprises phosphoric acid, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, perchloric acid, sulfuric acid, sulfurous acid, benzoic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, acrylic acid, propionic acid, pyruvic acid, oxalic acid, tartaric acid, dibenzoyl tartaric acid, p-methyldibenzoyl tartaric acid, malic acid, lactic acid, stearic acid and citric acid, and further preferably hydrochloric acid.
In the second step, the post-treatment is extraction and concentration of an organic phase after acidification, the crude product is dissolved in an aprotic organic solvent, and then organic base is added for precipitation and filtration; the organic base is selected from methylamine, ethylamine, propylamine, dimethylamine, diethylamine, diisopropylamine, dibutylamine, dicyclohexylamine, α -phenylethylamine, R-phenylethylamine, S-phenylethylamine, benzylamine, naphthylamine, 3-methylaminopropylamine, N '-dimethylethylenediamine, N N' -diethylethylenediamine, tetraethylenepentamine, cycleanine, triethylenetetramine, N-ethylethylenediamine, diethylenetriamine, and further preferably diethylamine.
And step three, reacting in an alkaline environment, after the reaction is finished, carrying out separation and drying post-treatment, and finally carrying out distillation purification to obtain a final product IV.
The reagent for the reaction used in the third step is selected from the group consisting of those containing R3The following compound of structure: benzenesulfonate of 1-3 carbon atoms1-6Alkyl substituted benzene sulfonate, carbonate, sulfate, triflate, bromohydrocarbon, iodohydrocarbon. Preferred reactants are methyl iodide, methyl p-toluenesulfonate, methyl benzenesulfonate, dimethyl carbonate, dimethyl sulfate, methyl trifluoromethanesulfonate, ethyl bromide, ethyl iodide, 1-bromopropane, 2-bromopropane, 1-bromobutane, 2-bromobutane, tert-butylchloride, tert-butylbromide, 1-bromopentane, 1-bromohexane, benzyl bromide, 4-methoxybenzyl bromide, 4-nitrobenzyl bromide, and finally preferably methyl p-toluenesulfonate.
The alkali in the third step comprises: sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, lithium carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, triethylamine, N-diisopropylethylamine, sodium hydride, DBU, and finally potassium bicarbonate is preferable.
The solvent in step three includes acetone, acetonitrile, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, ethyl formate, isopropyl acetate, N-butyl acetate, isobutyl acetate, tert-butyl acetate, methyl tert-butyl ether, methyl isobutyl ketone, and further preferably acetone.
The reaction temperature in the third step is-20-100 ℃, and the preferable temperature is 40-60 ℃;
the purification in the third step is not performed by column chromatography, and comprises filtration, extraction, washing and distillation; preferably, the final step is directed to a high purity final product by distillation. The distillation is selected from reduced pressure distillation and molecular distillation.
The halogen atom is selected from fluorine, chlorine, bromine and iodine.
The drying in the invention is drying by a vacuum oven or a blast air box, and other drying modes can be selected according to the production scale.
Compared with the prior art, the invention has the advantages that:
1. the raw materials are easy to obtain, the N-Boc-L-hydroxyproline is low in price and sufficient in market supply, the process is safe, and no virulent or high-risk reagent is used;
2. in the first step, water is used as a solvent, so that the use of an organic solvent and the environmental pollution caused by the organic solvent are greatly reduced, and the method is safe, environment-friendly and less in three wastes;
3. the post-treatment operation is simple, and a high-purity product can be obtained by distillation purification, wherein the purity of a gas phase exceeds 99%, and the ee value exceeds 99%, so that the high-end customer requirements are met;
4. the process has high efficiency and simple post-treatment, accelerates the productivity and meets the supply requirements of a large number of products;
5. the process has high efficiency and conventional equipment requirements, and is suitable for industrial scale-up production.
According to the method, N-protected L-proline is selected as a starting material, the raw material and an intermediate have carboxyl, and separation and purification are easily realized by simple means such as extraction, centrifugation and filtration by utilizing the solubility difference of carboxylic acid in an aqueous phase and an organic phase under acidic and alkaline conditions, so that the difficulty of subsequent separation and purification is greatly reduced.
Specifically, the method comprises the following steps: in the first step, only acidification is needed to separate out materials, and an intermediate can be obtained by filtration or extraction. After the diacid extraction, organic amine is added into the organic phase to form salt and precipitate, and then the refining is completed. And step three, adopting the traditional ester forming reaction, and finally purifying by molecular distillation equipment to obtain a product with the gas phase purity of more than or equal to 99% and the ee value of more than or equal to 99.0%.
In conclusion, the method has the advantages of easily available raw materials, simple and convenient operation, high overall yield, controllable three wastes, environmental friendliness and easy industrial production. The invention has important social value and economic value, and simultaneously provides guarantee for the production of downstream products and the industrial production and cost control of related medicines.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a 1H NMR spectrum of the product N-Boc-3, 4-dehydro-L-proline methyl ester of the present invention.
Detailed Description
The technical scheme of the invention is illustrated by the following specific embodiments, and the person skilled in the art can more clearly and intuitively understand the invention and provide greater help for the synthesis of the compounds.
Example 1
Figure BDA0003450842260000081
Adding water (150g) into a 1L three-necked bottle, adding sodium hydroxide (31g) under stirring, and cooling to 0-20 ℃ for later use after complete dissolution.
Adding the compound SM1(50g) into the alkali liquor, fully stirring and dissolving, and keeping the temperature of the system at 0-20 ℃.
To the system was added p-toluenesulfonyl chloride solid (TsCl, 66g), and the reaction was carried out at 0 to 20 ℃ for 2. + -. 1 hours.
After the reaction was completed, hydrochloric acid solution (1M,294g) was added to precipitate a product.
Filtration, the filter cake rinsed with water (50g), and the filtrate was filtered for disposal as a waste stream.
The filter cake was transferred to a tray and temperature controlled at 40-60 deg.C and air dried for 24 + -8 hours to give 68g of white solid with HPLC purity 98.3% and yield 82%.
Example 2
Figure BDA0003450842260000091
To a 100ml three-necked flask, SM1(5g) and methylene chloride (30g) were charged with stirring, and the temperature was lowered to 0 to 20 ℃.
Triethylamine (2.5g) was added dropwise, pivaloyl chloride (2.8g) was added dropwise, and the reaction was carried out at 0 to 20 ℃ for 1 hour.
Triethylamine (2.5g) was added dropwise again, followed by addition of a solution of 4-nitrobenzenesulfonyl chloride (NsCl, 5.5g) in dichloromethane (20g) and reaction at 0-20 ℃ for 1 hour.
After the reaction is finished, adding hydrochloric acid solution (0.5M,15.6g), adjusting the pH to 1-2, controlling the temperature to 10-30 ℃, and stirring for acidolysis for 2 +/-1 hours.
After the acidolysis reaction was completed, the mixture was allowed to stand for separation, the aqueous phase was extracted once more with dichloromethane (20g), and the organic phases were combined.
The organic phase was washed once with saturated brine (50g), and after separation, the organic phase was concentrated under reduced pressure to give an off-white solid (5.8 g), which had an HPLC purity of 97.6% and a yield of 64%.
Example 3
Figure BDA0003450842260000092
To a 100ml three-necked flask, SM1(5g) and methylene chloride (30g) were charged with stirring, and the temperature was lowered to 0 to 20 ℃.
Triethylamine (2.5g) and pivaloyl chloride (2.8g) were added dropwise thereto, followed by reaction at 0 to 20 ℃ for 1 hour.
Triethylamine (2.5g) was added dropwise again, followed by addition of a solution of methanesulfonyl chloride (MsCl, 2.8g) in dichloromethane (20g) and reaction at 0-20 ℃ for 2. + -.1 hour.
After the reaction is finished, adding hydrochloric acid solution (0.5M,15.6g), adjusting the pH to 1-2, controlling the temperature to 10-30 ℃, and stirring for acidolysis for 2 +/-1 hours.
After the acidolysis reaction was completed, the mixture was allowed to stand for separation, the aqueous phase was extracted once more with dichloromethane (20g), and the organic phases were combined.
The organic phase was washed once with saturated brine (50g), and after separation, the organic phase was concentrated under reduced pressure to give an oily liquid, which was recrystallized from a mixed solvent of isopropyl acetate and n-heptane (crude product of concentration: isopropyl acetate: 1g:1ml:2.5ml), to precipitate a white solid.
Filtering, leaching filter cakes by using a small amount of n-heptane, and treating filter liquor as waste liquor.
The filter cake was transferred to a tray and temperature controlled at 40-60 deg.C and air dried for 24 + -8 hours to give 5.2g of a white solid with HPLC purity 98.4% and yield 78%.
Example 4
Figure BDA0003450842260000101
While stirring, SM1(5g) and carbon tetrachloride (40g) were put into a 100ml three-necked flask and the temperature was lowered to 0-20 ℃.
Triethylamine (2.5g) was added dropwise, pivaloyl chloride (2.8g) was added dropwise, and the reaction was carried out at 0 to 20 ℃ for 1 hour.
Triphenylphosphine (PPh) was added to a three-necked flask with stirring36.8g), and controlling the temperature to be 0-20 ℃.
Diisopropyl azodicarboxylate (DIAD,5.2g) was added dropwise to the system, and the mixture was reacted at 0-20 ℃ for 16. + -. 2 hours.
After the reaction is finished, adding hydrochloric acid solution (0.5M,15.6g), adjusting the pH to 1-2, controlling the temperature to 10-30 ℃, and stirring for acidolysis for 2 +/-1 hours.
After quenching was complete, isopropyl acetate was extracted three times (20g x 3).
The organic phases were combined, washed once with saturated brine (50g), the organic phase was concentrated under reduced pressure after separation to give an oily liquid, which was purified by column separation to give 2.6g of a colorless oily substance with an HPLC purity of 87.6% and a yield of 48%.
TABLE 1 Synthesis of Compound II further examples are listed
Figure BDA0003450842260000111
Figure BDA0003450842260000121
Example 17:
Figure BDA0003450842260000131
adding toluene (261g), sodium methoxide (38g) and 2- [2- (dimethylamino) ethoxy ] ethanol (104g) into a 1L three-necked bottle, stirring and heating to 50-70 ℃ under the protection of Ar, reacting for 2h, distilling under reduced pressure until no obvious fraction is obtained, and adding acetonitrile (156g) into the obtained concentrated product to dissolve for later use.
Acetonitrile (390g) and 10 intermediates (100g) obtained in example 1 were added to a 2L three-necked flask, followed by stirring, cooling in an ice-water bath to 10 to 30 ℃ and adding the above concentrated acetonitrile solution to the system, and the temperature was controlled at 10 to 30 ℃ to react for 24. + -. 8 hours.
After completion of the reaction, water (300g) was added to the system, and after thoroughly stirring and dissolving, the system pH was adjusted to 2 to 3 with 10% hydrochloric acid solution (455g), and the reaction was acidified for 4 ± 2 hours at 10 to 30 ℃.
After the acidification was complete, it was extracted with methyl tert-butyl ether (185g x 2) and the aqueous phase was treated as waste.
The organic phase obtained was washed twice with water (300g x 2) and concentrated under reduced pressure until no significant fractions were obtained, giving 48g of a yellow oil.
Adding methyl tert-butyl ether (110g) to dissolve completely, controlling the temperature to be 10-30 ℃, dropwise adding diethylamine (13.2g), and reacting for 1h under the condition of heat preservation.
Filtration was carried out, the filter cake was rinsed with methyl tert-butyl ether (17.7g), and the filtrate was treated as waste.
47g of the obtained cake was dissolved in water (94g) and clarified, and 10% HCl (52g) was added dropwise thereto while controlling the temperature at 10 to 30 ℃ to adjust the pH to 2 to 3, followed by two-time extraction with methyl t-butyl ether (62 g. times.2).
The organic phases were combined and concentrated under reduced pressure until no significant fraction was observed, giving 36g of a pale yellow oil, a yield of 65% and an ee value of 99.7%.
Example 18:
Figure BDA0003450842260000141
specific experimental procedure reference is made to example 5, except that the elimination reaction is carried out using 2- [2- (dimethylamino) ethoxy ] ethanol instead of 2- [2- (dimethoxy) ethoxy ] ethanol, the yield of product being 57% and the ee value being 96.8%.
TABLE 2 list of other examples of Compounds III
Figure BDA0003450842260000142
Example 22
Figure BDA0003450842260000143
20 of the intermediate (1.3kg) obtained in example 5, acetone (10.4kg), potassium hydrogen carbonate (1.9kg) and methyl p-toluenesulfonate (1.0kg) were charged into a 20L four-necked reaction flask in this order, and the mixture was heated to 40 to 60 ℃ with stirring.
After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed twice with acetone (1.0 kg. times.2), the filtrates were combined and concentrated under reduced pressure until no significant fraction was observed.
To the above concentrate was added methyl t-butyl ether (8.2kg), and the mixture was thoroughly stirred to dissolve, and then washed three times with water (5.2 kg. times.3).
After the liquid separation, BHT (0.02%) as a stabilizer was added to the organic phase, and the mixture was concentrated under reduced pressure until no significant fraction was observed to obtain 1.2kg of a yellow oily liquid.
The obtained concentrated crude product was purified by molecular distillation (vacuum degree <10Pa), and 984g of main fraction was collected, GC purity was 99.2%, ee value was 99.5%, and yield was 70%.
Example 23
Figure BDA0003450842260000151
20 intermediate (5g) obtained in example 5, acetone (30g), potassium hydrogen carbonate (3.5g) and iodoethane (EtI, 10g) were added in this order to a 100ml three-necked flask, and the mixture was heated to 40 to 60 ℃ with stirring sufficiently to react for 4. + -. 1 hours.
After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed twice with acetone (5g x 2), the filtrates were combined and concentrated under reduced pressure until no significant fraction was observed.
To the above concentrate was added methyl t-butyl ether (30g), and the mixture was thoroughly stirred and dissolved, and then washed with water (30g × 3) three times.
Adding stabilizer BHT (0.02%) into the organic phase after liquid separation, concentrating under reduced pressure until no obvious fraction is obtained to obtain yellow oily liquid, performing high vacuum distillation purification (vacuum degree 200Pa) on the obtained concentrated crude product, collecting 3.1g of main fraction, wherein the GC purity is 97.4%, the ee value is 99.2%, and the yield is 55%.
Example 24
Figure BDA0003450842260000161
To a 100ml three-necked flask were added the 20-membered intermediate obtained in example 5 (5g), N, N-dimethylformamide (DMF, 30g), potassium carbonate (3.5g) and benzyl bromide (4g) in this order, and the reaction was stirred well at 40 to 60 ℃ for 16. + -. 4 hours.
After the reaction, the reaction solution was filtered, the filter cake was rinsed twice (5g x 2) with N, N-dimethylformamide, and the filtrates were combined and concentrated under reduced pressure until no significant fraction was observed.
To the above concentrate was added methyl t-butyl ether (30g), and the mixture was thoroughly stirred and dissolved, and then washed with water (30g × 3) three times.
After the liquid separation, the organic phase is subjected to pressure concentration until no obvious fraction is obtained, yellow oily liquid is obtained, and after column separation and purification, 3.6g of product is obtained, the GC purity is 96.6%, the ee value is 99.3%, and the yield is 50%.
Example 25
Figure BDA0003450842260000162
The procedure is as described in example 21, except that the carboxyl protecting group is exchanged from benzyl bromide to cyclopentyl bromide, and the resulting concentrated crude product is isolated and purified on a column with a GC purity of 92.3%, an ee of 99.1% and a yield of 45%.
TABLE 3 list of other examples of Compound IV
Figure BDA0003450842260000163
Figure BDA0003450842260000171
Comparative example 1
Figure BDA0003450842260000172
To a 100ml three-necked flask, SM1(5g), tetrahydrofuran (15g) and sodium hydroxide (3.1g) were charged with stirring, and the temperature was lowered to 0 to 20 ℃.
To the system was added dropwise a solution of p-toluenesulfonyl chloride (TsCl, 6.6g) in tetrahydrofuran (15g), and the reaction was carried out at 0 to 20 ℃ for 2. + -. 1 hours.
After the reaction was completed, a hydrochloric acid solution (1M,31.4g) was added to precipitate a product.
Filtration, the filter cake rinsed with water (10g), and the filtrate was filtered for disposal as a waste stream.
The filter cake was transferred to a tray and temperature controlled at 40-60 deg.C and air dried for 24 + -8 hours to give 3.6g of white solid with HPLC purity 96.3% and yield 43%.
Comparative example 2
Adding toluene (261g), sodium methoxide (38g) and 2- [2- (dimethylamino) ethoxy ] ethanol (104g) into a 1L three-necked bottle, stirring and heating to 50-70 ℃ under the protection of Ar, reacting for 2h, distilling under reduced pressure until no obvious fraction is obtained, and adding acetonitrile (156g) into the obtained concentrated product to dissolve for later use.
Acetonitrile (390g) and the 10-intermediate (100g) obtained in example 1 were added to a 2L three-necked flask, and stirred thoroughly, and the temperature was controlled at 50 to 70 ℃ to add the above-mentioned concentrated acetonitrile solution to the system, and the temperature was controlled at 50 to 70 ℃ to react for 24. + -. 8 hours.
After completion of the reaction, water (300g) was added to the system, and after thoroughly stirring and dissolving, the system pH was adjusted to 2 to 3 with 10% hydrochloric acid solution (455g), and the reaction was acidified for 4 ± 2 hours at 10 to 30 ℃.
After the acidification was complete, extraction was performed with methyl tert-butyl ether (185g x 2) and the aqueous phase was treated as waste.
The organic phase obtained was washed twice with water (300g x 2) and concentrated under reduced pressure until no significant fractions were obtained, giving 48g of a yellow oil.
Adding methyl tert-butyl ether (110g) to dissolve completely, controlling the temperature to be 10-30 ℃, dropwise adding diethylamine (13.2g), and reacting for 1h under the condition of heat preservation.
Filtration was carried out, the filter cake was rinsed with methyl tert-butyl ether (17.7g), and the filtrate was treated as waste.
47g of the obtained cake was dissolved in water (94g) and clarified, and 10% HCl (52g) was added dropwise thereto while controlling the temperature at 10 to 30 ℃ to adjust the pH to 2 to 3, followed by two-time extraction with methyl t-butyl ether (62 g. times.2).
The organic phases were combined and concentrated under reduced pressure until no significant fraction was observed, giving 36g of a pale yellow oil, 48% yield and 60.7% ee.
Comparative example 3
Figure BDA0003450842260000191
Acetonitrile (20g) and 10g of the intermediate (5g) obtained in example 1 were added to a 100ml three-necked flask, and the mixture was stirred well, cooled to 10 to 30 ℃ in an ice water bath, and potassium tert-butoxide (3.9g) was added to the system and reacted at 10 to 30 ℃ for 24. + -. 8 hours.
The workup was as in example 17, giving a yield of 42% and an ee of 50.1%.
Comparative example 4
Figure BDA0003450842260000192
Detailed description of the preferred embodimentsreferring to example 22, the concentrated crude product obtained was purified by high vacuum distillation (vacuum 200Pa) with a GC purity of 95.0%, an ee of 99.2% and a yield of 58%.
Comparative example 5
Figure BDA0003450842260000201
Referring to example 22, the concentrated crude product was purified by column separation, and the product had a GC purity of 99.3%, an ee value of 99.4%, and a yield of 52%.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.

Claims (10)

1. A process for the synthesis of an N-protected 3, 4-dehydro-L-proline ester, comprising the steps of:
Figure FDA0003450842250000011
the method comprises the following steps: using a compound shown in a formula I as a starting material, and reacting to obtain an intermediate compound shown in a formula II;
step two: the intermediate compound shown in the formula II reacts under an alkaline condition to generate an intermediate compound shown in the formula III;
step three: reacting the intermediate compound shown in the formula III into ester to obtain a compound shown in the formula IV, namely N-protected 3, 4-dehydro-L-proline ester;
R1selected from amino protecting groups;
R2selected from fluorine, chlorine, bromine, iodine, or substituted sulfonyl selected from C1-6A sulfonyl group substituted with a hydrocarbon group, a benzenesulfonyl group whose benzene ring may be substituted with 1 to 3C1-6Hydrocarbyl radical, C1-6Alkoxy, halogen and nitro;
R3is selected from C1-10Straight or branched chain hydrocarbon radical, C3-10Cycloalkyl radical, C6-10Aryl or heteroaryl, said C1-10The straight-chain or branched hydrocarbon radicals may be substituted by 1 to 3 halogen atoms or C3-6Cycloalkyl, phenyl,Methylphenyl, ethylphenyl, said C3-10Cycloalkyl radical, C6-10The aryl or heteroaryl radical may be substituted by 1 to 3C1-6Hydrocarbyl, alkoxy, halogen or nitro.
2. The method of claim 1, wherein:
R1selected from Boc, Cbz, Bn, Bz, Fmoc, Alloc, Teoc, Ts, Tfa, Trt, Dmb, PMB or Pht, preferably Boc;
R2selected from the group consisting of methanesulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-methoxybenzenesulfonyl, 2-chlorobenzenesulfonyl, 2-fluorobenzenesulfonyl, 2, 6-dichlorobenzenesulfonyl, 2,4, 6-trichlorobenzenesulfonyl, 4-bromo-2-chlorobenzenesulfonyl, 2, 3-dichlorobenzenesulfonyl, 3-chlorobenzenesulfonyl, 3, 5-dichlorobenzenesulfonyl, 4-chlorobenzenesulfonyl, 2,4, 5-trichlorobenzenesulfonyl, 2, 4-dichlorobenzenesulfonyl, 3, 4-dichloromethylsulfonyl, 5-chloro-2, 4-difluorobenzenesulfonyl, 4-chloro-3-nitrobenzenesulfonyl, 3-bromobenzenesulfonyl, 2-bromobenzenesulfonyl, 4-bromobenzenesulfonyl, 4-bromo-3-fluorobenzenesulfonyl, 4-bromo-2-fluorobenzenesulfonyl, 4-nitrobenzenesulfonyl, 2-nitrobenzenesulfonyl and 3-nitrobenzenesulfonyl, and is further preferably p-methylbenzenesulfonyl;
R3preferably methyl, ethyl, propyl, isopropyl, n-butyl, 2-sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, cyclohexyl, phenyl, benzyl, 4-methoxybenzyl, 4-nitrobenzyl, benzhydryl, trityl, 4-picolyl, beta-trichloroethyl, beta-methyl-thioethyl, beta-p-toluenesulfonylethyl, beta-p-nitrophenylthioethyl, trimethylsilyl, tert-butyldimethylsilyl, triethylsilyl, propargyl; methyl and ethyl are particularly preferred.
3. The process of claim 1 or 2, wherein the reaction solvent of step one is water, and the compound of formula I is directly reacted with the reaction reagent; or the reaction solvent in the first step is an organic solvent, the compound in the formula I is firstly protected by pivaloyl chloride and then reacts with the reaction reagent, and pivaloyl is hydrolyzed and removed in the post-treatment process.
4. The method of claim 3, wherein when the reaction solvent is water, the compound of formula II is obtained by acidification, filtration and drying after the reaction of step one; when the reaction solvent is an organic solvent, acidolysis and extraction are required.
5. The method according to claim 1, wherein the reaction temperature in the second step is-20 to 60 ℃, and more preferably 10 to 30 ℃.
6. The process of claim 1, wherein the reaction solvent used in step two is selected from one or more of acetone, acetonitrile, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide and 1, 3-dimethyl-2-imidazolidinone, and is preferably acetonitrile.
7. The method of claim 1, wherein the post-treatment in the second step is extraction after acidification and organic phase concentration, the crude product is dissolved in an aprotic organic solvent, and then an organic base is added for precipitation and filtration; the organic base is selected from methylamine, ethylamine, propylamine, dimethylamine, diethylamine, diisopropylamine, dibutylamine, dicyclohexylamine, α -phenylethylamine, R-phenylethylamine, S-phenylethylamine, benzylamine, naphthylamine, 3-methylaminopropylamine, N '-dimethylethylenediamine, N N' -diethylethylenediamine, tetraethylenepentamine, cycleanine, triethylenetetramine, N-ethylethylenediamine, diethylenetriamine, and further preferably diethylamine.
8. The method according to claim 1, wherein the reaction temperature in step three is-20 to 100 ℃, and more preferably 40 to 60 ℃.
9. The method of claim 1, wherein the final product is obtained by distillation without column chromatography after the reaction of step three.
10. The method of claim 9, wherein the distillation is molecular distillation.
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CN115160205A (en) * 2022-07-08 2022-10-11 上海皓鸿生物医药科技有限公司 Method for preparing (S) -1- (tert-butyloxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salt thereof

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