CN114105848A - Preparation method of cis-D-hydroxyproline derivative - Google Patents

Preparation method of cis-D-hydroxyproline derivative Download PDF

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CN114105848A
CN114105848A CN202111409287.XA CN202111409287A CN114105848A CN 114105848 A CN114105848 A CN 114105848A CN 202111409287 A CN202111409287 A CN 202111409287A CN 114105848 A CN114105848 A CN 114105848A
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严利民
焦波
燕青
陈纹锐
张丽
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Sichuan Tongsheng Biopharmaceutical Co ltd
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    • 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
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Abstract

The invention discloses a preparation method of a cis-D-hydroxyproline derivative, relates to the technical field of organic chemistry, and solves the technical problems that the existing cis-D-hydroxyproline derivative is complex in synthesis process, high in requirement on equipment and not beneficial to large-scale industrial production; the preparation method comprises the following steps: the method comprises the following steps of taking 3-bromopropylene and chiral arylamine which are economical and easy to obtain as starting raw materials, firstly synthesizing to obtain intermediate chiral amine, then closing the ring with glyoxylic acid to obtain hydroxyproline lactone protected by racemate N, obtaining a single chiral purity product through resolution by a chiral acid resolving agent, and finally opening the ring and performing deprotection to obtain a final target product; compared with the prior art, the method has the advantages that the five-membered ring is constructed by the method, two chiral isomeric products are obtained, the required target product can be selectively split according to the requirement, the operability is strong, the process route is simple, and the method has an industrial amplification prospect.

Description

Preparation method of cis-D-hydroxyproline derivative
Technical Field
The invention relates to the technical field of organic chemistry, in particular to the technical field of synthesis of cis-D-hydroxyproline derivatives.
Background
L-hydroxyproline is a non-essential amino acid for human body, and can be prepared in large quantity by a fermentation method at present, cis-D-hydroxyproline cannot be prepared by a fermentation method, so that the cis-D-hydroxyproline can be prepared only by a chemical synthesis method, and a main route for preparing cis-D-hydroxyproline reported at present is as follows:
1. U.S. patent US2004/77879 reports a synthetic route to cis-D-hydroxyproline as follows:
Figure BDA0003371086890000011
the method uses trans-L-hydroxyproline as a raw material, and comprises the steps of closing cyclization by acetic anhydride, then carrying out acid hydrolysis and ring opening deprotection to obtain cis-D-hydroxyproline, wherein a large amount of acetic anhydride and acetic acid are used in the process of the method, and a large amount of alkali is used for neutralization in the post-treatment; and the irritation of acetic anhydride is very large; in the hydrolysis step, a large amount of hydrochloric acid is used, so that the equipment is relatively corrosive and has high requirements on the equipment.
2.2002 Kimura, Rumi; nagano, Tanemasa; kinoshita (Hidekibulletin of the Chemical Society of Japan2002vol.75#11 p.2517-2525) et al propose the following scheme:
Figure BDA0003371086890000012
however, the final product is obtained by nine steps of reaction in the route, the route is long, and operations such as nitrogen protection are needed in the process, which is not beneficial to large-scale industrial production.
Based on the defects, the invention provides the synthesis method which has high operability and simple process steps and is suitable for industrial production.
Disclosure of Invention
The invention aims to: in order to solve the above technical problems, the present invention provides a method for preparing a cis-D-hydroxyproline derivative.
The invention specifically adopts the following technical scheme for realizing the purpose:
a preparation method of a cis-D-hydroxyproline derivative comprises the following steps:
(1) adding potassium carbonate and potassium iodide into aromatic amine and 3-bromopropylene in a solvent, and heating to react to obtain an intermediate 3 (chiral amine);
(2) the intermediate 3 reacts with glyoxylic acid to close the ring to obtain intermediates 4 and 5 (hydroxyproline lactone protected by racemate N);
(3) dissolving the mixture of the intermediates 4 and 5 in a solvent, and adding a chiral resolving agent for resolution to obtain a single chiral product intermediate 5;
(4) dissolving the intermediate 5 in a solvent, and adding thionyl chloride for ring opening to obtain an intermediate 6;
(5) adding a catalyst into the intermediate 6 for deprotection, and reacting with Boc anhydride or Z-OSU to obtain a target product;
the structural formula of the aromatic amine is R-NH2，
The structural formula of the target product is
Figure BDA0003371086890000021
Wherein the content of the first and second substances,
Figure BDA0003371086890000022
R1boc (tert-butyloxycarbonyl protecting group) or Cbz (benzyloxycarbonyl protecting group).
Preferably, the aromatic amine is selected from benzylamine, chiral phenethylamine, chiral phenylglycinol or benzhydrylamine, more preferably chiral phenethylamine.
Preferably, the reaction temperature of the step (1) is 80-100 ℃, more preferably 90-100 ℃, and the reaction time is 8-24h, more preferably 16-24 h.
Preferably, the solvent of step (1) is selected from DMF, DMAC or DMSO, more preferably DMF.
Preferably, in the step (1), the reaction molar ratio of the aromatic amine to the 3-bromopropene is 1 (1.1-1.50), more preferably 1 (1.2-1.3); the reaction molar ratio of the aromatic amine to the potassium carbonate is 1 (2.5-4.0), more preferably 1 (3.5-4.0), and the reaction molar ratio of the aromatic amine to the potassium iodide is 1 (0.5-1.0), more preferably 1 (0.8-1.0).
Preferably, in the step (2), the reaction molar ratio of the intermediate 3 to the glyoxylic acid is 1 (1.1-1.5), and more preferably 1 (1.4-1.5).
Preferably, in the step (2), the reaction temperature is 50-65 ℃, more preferably 60-65 ℃; the reaction time is 2-6h, more preferably 4-6 h.
Preferably, in the step (3), the chiral resolving agent is selected from tartaric acid, camphorsulfonic acid or camphoric acid, and the molar ratio of the mixture of intermediates 4 and 5 to the chiral resolving agent is 0.8 to 1.2, more preferably 1.0 to 1.1.
Preferably, in the step (4), the molar ratio of the intermediate 5 to the thionyl chloride is 1 (2.0-3.0), and more preferably 1 (2.5-3.0).
Preferably, in the step (4), the reaction time is 8-16h, and more preferably 12-16 h; the reaction temperature is 50 to 65 ℃ and more preferably 60 to 65 ℃.
Preferably, in the step (5), the catalyst is selected from palladium carbon, palladium hydroxide or raney nickel, more preferably palladium carbon; the reaction time is 8-24h, and more preferably 20-24 h; the reaction temperature is 30-50 ℃, and more preferably 45-50 ℃; the reaction pressure is 3 to 5MPa, more preferably 4.5 to 5 MPa.
The invention has the following beneficial effects:
1. the method takes the 3-bromopropylene and the chiral arylamine as the initial raw materials, the raw materials are economic and easy to obtain, the target product is obtained through 5 steps, the synthetic route is simplified, the process steps are simple, irritant and corrosive substances such as acetic acid, acetic anhydride and the like are not used, the corrosion to equipment is small, the requirement on the equipment is not high, and the method is suitable for industrial production.
2. Compared with the prior art, the method has the advantages that the five-membered ring is constructed by the method, two chiral isomeric products are obtained, the required target product can be selected and resolved according to requirements, the operability is strong, and the method has an industrial amplification prospect.
Drawings
FIG. 1 is a synthetic scheme for the preparation of Compound 7 in example 5;
FIG. 2 is a photograph of Compound 7 obtained in example 51An H-NMR spectrum;
FIG. 3 is a synthetic scheme for the preparation of Compound 8 in example 7;
FIG. 4 is a photograph of Compound 8 obtained in example 71H-NMR spectrum.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the embodiments, and it is obvious that the described embodiments are some, but not all embodiments of the present invention.
Thus, the following detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Synthesis of Compound 3
1500mL of DMF, 174g R-alpha-phenylethylamine (chiral phenylethylamine) and 600g of potassium carbonate are added into a 3L three-necked flask with mechanical stirring, the mixture is stirred for 10 minutes after the addition, 150g of 3-bromopropylene is added dropwise, 205g of potassium iodide is added, the temperature is increased to 90-95 ℃ for reaction for 16-24 hours, and the reaction is monitored to be complete by TLC. Cooling to 20-25 ℃, filtering, washing a filter cake with petroleum ether, adding 3L of water into filtrate, extracting with petroleum ether (2 x 500mL), combining organic phases, washing with salt, drying, filtering, concentrating until no fraction is produced, adding 1L of ethyl acetate for dissolving, cooling to 0-10 ℃, dropwise adding an ethyl acetate hydrogen chloride solution to adjust the pH to 4-5, stirring for 30 minutes, filtering to obtain a white-like solid, adding into 500mL of water, adjusting the pH with sodium carbonate, extracting with petroleum ether, combining the organic phases, drying, filtering, concentrating until the mixture is dry, obtaining 162.5g of a compound 3 yellowish-brown oily substance, the yield is 81.3%, and the purity: 95 percent.
Example 2
Synthesis of mixtures of Compounds 4 and 5
Adding 180g of compound 3 in the embodiment 1 into a 2000mL round bottom flask provided with a reflux pipe and a thermometer, cooling to 0-5 ℃, controlling the temperature to be 0-20 ℃, dropwise adding 310g of 40% glyoxylic acid aqueous solution, heating to 60-65 ℃ after completing dropwise adding, reacting for 4-6h, and monitoring the reaction completion by TLC. Concentrating tetrahydrofuran to dryness, adding water and petroleum ether, separating liquid, extracting with 500mL petroleum ether once, combining organic phases, washing twice with saturated sodium bicarbonate water solution, washing once with saturated salt solution, combining organic phases, drying, filtering and concentrating to dryness to obtain 159g of brown oily matter of a mixture of the compound 4 and the compound 5, wherein the yield is 65.6 percent and the purity is 98.6 percent.
Example 3
Synthesis of Compound 5
Adding 500mL of methanol and 500mL of ethanol into a 2L three-necked flask with magnetic stirring, adding 100g of the mixture of the compounds 4 and 5 in the example 2, adding 107g R-camphorsulfonic acid, stirring for dissolving, continuing stirring for 20-24h at 20-30 ℃, filtering, and adding methanol: washing with a 1:1 mixed solvent to give 80g of an off-white solid, yield: 39.6 percent. Dissolving in water, adding ammonia water to adjust pH, and extracting with petroleum ether to obtain compound 5, yellow oil, ee: 99.3%, purity: 99.12 percent
Example 4
Synthesis of Compound 6
A1000 mL three-necked flask equipped with a reflux tube and a thermometer was charged with 300mL of methanol and 30g of the compound 5 of example 3, and 41.3g of thionyl chloride was slowly added dropwise while maintaining T < 20 ℃ and after the addition was completed, the temperature was raised to 60-65 ℃ for reaction. TLC starting material was reacted and concentrated under reduced pressure to no fractions, 200mL water was added, pH was adjusted to 8-9 with sodium carbonate, MTBE (2 x 100mL) was extracted, the organic phases were combined, washed with salt, dried and concentrated to give compound 6 as a pale yellow oil 32.7g, yield: 95%, purity: 98.6 percent.
Example 5
Synthesis of Compound 7
300mL of methanol, 60mL of water, 30g of the compound 6 obtained in example 4, 31.5g of Boc anhydride, 15g of sodium bicarbonate and 3.2g of palladium on carbon were added to a 500mL autoclave, hydrogen gas was added to the autoclave after nitrogen substitution, the temperature was raised to 40-45 ℃ to react for 24 hours or more, the TLC material was reacted completely, the reaction solution was taken out, methanol was removed by concentration, MTBE was extracted, drying, filtration and concentration were carried out to obtain an oily substance, and petroleum ether was crystallized to obtain a compound 7 (target product) as a white-like solid24.1g, yield: 82%, purity: 99.6 percent.1H-NMR(400MHz,CDCl3)4.40-4.28(m, 2H); 3.79(d, 3H); 3.74-3.60(m, 1H); 3.57-3.46(m, 1H); 2.41-2.26(m, 1H); 2.14-2.03(m, 2H); 1.45(d,9H), as shown in fig. 2.
Example 6
Synthesis of Compound 7
300mL of methanol, 60mL of water, 30g of the compound 6 of example 4, 31.5g of Boc anhydride, 15g of sodium bicarbonate and 3.2g of palladium hydroxide were placed in a 500mL autoclave, after replacement with nitrogen, 4.5-5.0MPa of hydrogen was added, the temperature was raised to 40-45 ℃ to react for 24 hours or more, after completion of the TLC reaction, the reaction mixture was taken out, the methanol was removed by concentration, MTBE was extracted, dried, filtered and concentrated to give an oil, and petroleum ether was crystallized to give the compound 7 (target product) as an off-white solid (23.0 g, yield: 78.6 percent.
Example 7
Synthesis of Compound 8
Adding 300mL of methanol, 60mL of water and 30g of the compound 6 and 3.2g of palladium carbon in example 4 into a 500mL autoclave, replacing nitrogen, adding 4.5-5.0Mpa of hydrogen, heating to 40-45 ℃ for reaction for more than 24h, taking out reaction liquid after TLC raw material reaction is finished, adding 30g of sodium bicarbonate and 36gZ-OSU (benzyl-N-succinimidyl carbonate), reacting at room temperature for 20-24h, extracting with ethyl acetate, washing with salt, drying, filtering and concentrating to obtain an oily substance, crystallizing with petroleum ether to obtain a compound 8 (target product), 23.6g of an off-white solid, and obtaining the yield: 71 percent.1H-NMR(400MHz,CDCl3) δ 7.32(dd,5H),5.20(d,1H),5.08(dd,1H),4.43(dd,2H), 3.90-3.51 (m,5H),2.87(s,1H), 2.40-2.25 (m,1H),2.13(d,1H), as shown in FIG. 4.

Claims (10)

1. A method for preparing a cis-D-hydroxyproline derivative is characterized by comprising the following steps:
(1) adding potassium carbonate and potassium iodide into aromatic amine and 3-bromopropylene in a solvent, and heating to react to obtain an intermediate 3;
(2) the intermediate 3 reacts with glyoxylic acid to obtain intermediates 4 and 5;
(3) dissolving the mixture of the intermediates 4 and 5 in a solvent, and adding a chiral resolving agent for resolution to obtain an intermediate 5;
(4) dissolving the intermediate 5 in a solvent, and adding thionyl chloride for ring opening to obtain an intermediate 6;
(5) adding a catalyst into the intermediate 6 for deprotection, and reacting with Boc anhydride or Z-OSU to obtain a target product;
the structural formula of the aromatic amine is R-NH2，
The structural formula of the target product is
Figure FDA0003371086880000011
Wherein the content of the first and second substances,
Figure FDA0003371086880000012
R1boc or Cbz.
2. The method according to claim 1, wherein the aromatic amine is selected from benzylamine, chiral phenethylamine, chiral phenylglycinol or benzhydrylamine.
3. The method for preparing a cis-D-hydroxyproline derivative according to claim 1, wherein the reaction temperature in the step (1) is 80-100 ℃ and the reaction time is 8-24 h.
4. The process according to claim 1, wherein in the step (1), the aromatic amine and 3-bromopropene are reacted at a molar ratio of 1 (1.1 to 1.50), the aromatic amine and potassium carbonate are reacted at a molar ratio of 1 (2.5 to 4.0), and the aromatic amine and potassium iodide are reacted at a molar ratio of 1 (0.5 to 1.0).
5. The method according to claim 1, wherein the reaction molar ratio of the intermediate 3 to glyoxylic acid in step (2) is 1 (1.1-1.5).
6. The method for preparing a cis-D-hydroxyproline derivative according to claim 1, wherein in the step (2), the reaction temperature is 50-65 ℃ and the reaction time is 2-6 h.
7. The method according to claim 1, wherein in the step (3), the chiral resolving agent is selected from tartaric acid, camphorsulfonic acid or camphoric acid, and the molar ratio of the mixture of intermediates 4 and 5 to the chiral resolving agent is 0.8-1.2.
8. The process according to claim 1, wherein the molar ratio of the intermediate 5 to thionyl chloride in the step (4) is 1 (2.0-3.0).
9. The method for preparing a cis-D-hydroxyproline derivative according to claim 1, wherein the reaction time in the step (4) is 8 to 16 hours, and the reaction temperature is 50 to 65 ℃.
10. The method according to claim 1, wherein in the step (5), the catalyst is selected from palladium on carbon, palladium hydroxide or Raney nickel, the reaction time is 8-24h, the reaction temperature is 30-50 ℃, and the reaction pressure is 3-5 MPa.
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