CN114105848B - Preparation method of cis-D-hydroxyproline derivative - Google Patents

Preparation method of cis-D-hydroxyproline derivative Download PDF

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CN114105848B
CN114105848B CN202111409287.XA CN202111409287A CN114105848B CN 114105848 B CN114105848 B CN 114105848B CN 202111409287 A CN202111409287 A CN 202111409287A CN 114105848 B CN114105848 B CN 114105848B
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cis
reaction
hydroxyproline derivative
hydroxyproline
chiral
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CN114105848A (en
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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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    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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 equipment requirement and unfavorable for large-scale industrial production; the preparation method of the invention comprises the following steps: the preparation method comprises the steps of taking economic and easily available 3-bromopropene and chiral aromatic amine as starting materials, firstly synthesizing to obtain an intermediate chiral amine, then closing a ring with glyoxylate to obtain a hydroxyproline lactone protected by a raceme N, carrying out resolution by a chiral acid resolving agent to obtain a single chiral purity product, and finally opening a ring and removing protection to obtain a final target product; compared with the prior art, the invention constructs five-membered rings by itself to obtain two chiral isomerism products, and the required target products can be selectively resolved according to the requirements, so that the invention has strong operability and simple process route and has industrial amplifying 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 an unnecessary amino acid for human body, and is prepared in large quantity by a fermentation method at present, while cis-D-hydroxyproline cannot be prepared by the fermentation method, so that the L-hydroxyproline can only be prepared by a chemical synthesis mode, and the main preparation route of the cis-D-hydroxyproline reported at present is as follows:
1. U.S. patent 2004/77879 reports a cis-D-hydroxyproline synthesis route as follows:
the method comprises the steps of taking trans-L-hydroxyproline as a raw material, cyclizing through acetic anhydride, then carrying out acid hydrolysis, ring opening and 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 needed for neutralization in post-treatment; the acetic anhydride has great irritation; in the hydrolysis step, because a large amount of hydrochloric acid is used, the hydrolysis method has high corrosiveness to equipment and high requirements on the equipment.
Kimura, rumi, 2.2002; nagano, tanemasa; kinoshita (HidekiBulletin of the Chemical Society of Japan2002vol.75#11p.2517-2525) et al propose the following route:
however, the final product is obtained through nine steps of reactions, the route is long, and the operation such as nitrogen protection is needed in the process, so that the method is not beneficial to large-scale industrial production.
Based on the defects, the invention provides a synthesis method which has high operability and simple process steps and is suitable for industrial production.
Disclosure of Invention
The invention aims at: in order to solve the technical problems, the invention provides a preparation method of a cis-D-hydroxyproline derivative.
The invention adopts the following technical scheme for realizing the purposes:
a process for the preparation of a cis-D-hydroxyproline derivative, which comprises the steps of:
(1) Adding potassium carbonate and potassium iodide into aromatic amine and 3-bromopropene in a solvent, and heating to react to obtain an intermediate 3 (chiral amine);
(2) Intermediate 3 is reacted with glyoxylate to close the ring to give intermediates 4 and 5 (racemic N-protected hydroxyproline lactone);
(3) The mixture of the intermediates 4 and 5 is dissolved in a solvent, and a chiral resolving agent is added 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 simultaneously reacting with Boc anhydride or Z-OSU to obtain a target product;
the structural formula of the aromatic amine is R-NH 2 ，
The structural formula of the target product is
Wherein,
R 1 is Boc (t-butoxycarbonyl protecting group) or Cbz (benzyloxycarbonyl protecting group).
Preferably, the aromatic amine is selected from benzylamine, chiral phenethylamine 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 16-24h.
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 molar ratio of aromatic amine to potassium carbonate is 1 (2.5-4.0), more preferably 1 (3.5-4.0), and the molar ratio of aromatic amine to 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 glyoxylate is 1 (1.1-1.5), more preferably 1 (1.4-1.5).
Preferably, in the step (2), the reaction temperature is 50 to 65 ℃, more preferably 60 to 65 ℃; the reaction time is 2 to 6 hours, more preferably 4 to 6 hours.
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 0.8-1.2, more preferably 1.0-1.1.
Preferably, in the step (4), the molar ratio of the reaction of the intermediate 5 with thionyl chloride is 1 (2.0-3.0), more preferably 1 (2.5-3.0).
Preferably, in the step (4), the reaction time is 8 to 16 hours, more preferably 12 to 16 hours; 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 to 24 hours, more preferably 20 to 24 hours; the reaction temperature is 30-50 ℃, more preferably 45-50 ℃; the reaction pressure is 3 to 5MPa, more preferably 4.5 to 5MPa.
The beneficial effects of the invention are as follows:
1. according to the invention, 3-bromopropene and chiral aromatic amine are used as starting materials, the raw materials are economical and easy to obtain, the target product is obtained through 5 steps, the synthetic route is simplified, the process steps are simple, no pungent and corrosive substances such as acetic acid and acetic anhydride are used, the corrosiveness to equipment is small, the requirement on equipment is low, and the method is suitable for industrial production.
2. Compared with the prior art, the invention constructs five-membered rings by itself to obtain two chiral isomerism products, and the required target products can be selectively resolved according to the requirements, so that the invention has strong operability and industrial amplification prospect.
Drawings
FIG. 1 is a synthetic scheme for the preparation of compound 7 in example 5;
FIG. 2 is a diagram of Compound 7 obtained in example 5 1 H-NMR spectrum;
FIG. 3 is a synthetic scheme for the preparation of compound 8 in example 7;
FIG. 4 is a diagram of compound 8 prepared in example 7 1 H-NMR spectrum.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments.
Thus, the following detailed description of the embodiments of the 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 made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Synthesis of Compound 3
1500mL DMF,174g R-alpha-phenethylamine (chiral phenethylamine), 600g of potassium carbonate and 150g of 3-bromopropene are added into a 3L three-necked flask with mechanical stirring, stirring is carried out for 10 minutes after the addition, 205g of potassium iodide is added, the temperature is raised to 90-95 ℃ for reaction for 16-24 hours, and TLC monitoring is carried out for complete reaction. Cooling to 20-25 ℃, filtering, flushing a filter cake with petroleum ether, adding 3L of water into the filtrate, extracting with petroleum ether (2 x 500 mL), merging organic phases, washing with salt, drying, filtering, concentrating until no fraction is present, adding 1L of ethyl acetate for dissolution, cooling to 0-10 ℃, dropwise adding ethyl acetate hydrogen chloride solution for regulating pH to 4-5, stirring for 30 min, filtering to obtain an off-white solid, adding into 500mL of water, regulating pH with sodium carbonate, extracting with petroleum ether, merging organic phases, drying, filtering, concentrating to dryness, and obtaining 162.5g of compound 3 as a yellowish brown oily substance with the yield of 81.3%, purity: 95%.
Example 2
Synthesis of mixtures of Compounds 4 and 5
A2000 mL round bottom flask equipped with a reflux tube and a thermometer is added with 900mL tetrahydrofuran 180g of the compound 3 in the embodiment 1, the temperature is reduced to 0-5 ℃, 310g of 40% glyoxylate aqueous solution is added dropwise at the temperature of 0-20 ℃, the temperature is increased to 60-65 ℃ after the dripping is finished, the reaction is carried out for 4-6 hours, and TLC monitoring is carried out for the reaction to completion. Concentrating tetrahydrofuran to dryness, adding water and petroleum ether, separating liquid, extracting once with 500mL petroleum ether, combining organic phases, washing twice with saturated sodium bicarbonate aqueous solution and once with saturated salt water, combining organic phases, drying, filtering, concentrating to dryness, and obtaining 159g brown oily substance of a mixture of the compounds 4 and 5, wherein the yield is 65.6% and the purity is 98.6%.
Example 3
Synthesis of Compound 5
500mL of methanol and 500mL of ethanol were added to a 2L three-necked flask equipped with magnetic stirring, 100g of a mixture of the compounds 4 and 5 of example 2 was further added, 107g R-camphorsulfonic acid was added, stirring was continued for 20-24 hours at 20-30℃after dissolution, filtration was carried out, and the cake was purified by methanol: ethanol=1:1 mixed solvent rinse, yielding 80g of off-white solid, yield: 39.6%. Dissolving in water, adding ammonia water to adjust pH, extracting with petroleum ether to obtain compound 5 as yellow oily substance, ee:99.3%, purity: 99.12%
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 Compound 5 of example 3, and 41.3g of thionyl chloride was slowly added dropwise at a temperature of less than 20℃and the reaction was carried out at a temperature of 60-65 ℃. After the TLC starting material was reacted, the reaction mixture was concentrated under reduced pressure until no fraction was obtained, 200mL of water was added, pH was adjusted to 8-9 with sodium carbonate, mtbe (2 x 100 mL) 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%.
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, 3.2g of palladium on carbon, 4.5-5.0MPa of hydrogen after nitrogen substitution, heating to 40-45 ℃ for more than 24 hours, taking out the reaction liquid after TLC raw material reaction, concentrating to remove methanol, extracting MTBE, drying, filtering, concentrating to obtain oily matter, crystallizing petroleum ether to obtain compound 7 (target product), and obtaining 24.1g of off-white solid with yield: 82%, purity: 99.6%. 1 H-NMR(400MHz,CDCl 3 ) 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 compound 6 in example 4, 31.5g of Boc anhydride, 15g of sodium bicarbonate, 3.2g of palladium hydroxide, hydrogen after nitrogen substitution, 4.5-5.0MPa are added into a 500mL autoclave, the temperature is raised to 40-45 ℃ for more than 24 hours, the TLC raw materials are reacted completely, the reaction liquid is taken out, methanol is removed by concentration, MTBE extraction, drying and filtration are carried out, oily matters are obtained by concentration, petroleum ether is crystallized to obtain compound 7 (target product), off-white solid is 23.0g, and the yield is: 78.6%.
Example 7
Synthesis of Compound 8
300mL of methanol and 60mL of water are added into a 500mL autoclave, 30g of compound 6 in example 4, 3.2g of palladium on carbon are replaced by nitrogen, hydrogen is added into the autoclave to react for more than 24 hours at the temperature of 40-45 ℃ under 4.5-5.0Mpa, after the TLC raw materials are reacted, the reaction liquid is taken out, 30g of sodium bicarbonate and 36gZ-OSU (benzyl-N-succinimidyl carbonate) are added into the reaction liquid to react for 20-24 hours at room temperature, ethyl acetate extraction, salt washing, drying, filtration and concentration are carried out to obtain oily matters, petroleum ether crystallization is carried out to obtain compound 8 (target product), off-white solid 23.6g is obtained, and the yield is: 71%. 1 H-NMR(400MHz,CDCl 3 ) Delta 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 (9)

1. A process for the preparation of a cis-D-hydroxyproline derivative, comprising the steps of:
(1) Adding potassium carbonate and potassium iodide into aromatic amine 1 and 3-bromopropene in a solvent, and heating to react to obtain an intermediate 3;
(2) Intermediate 3 reacts with glyoxylate to close the ring to obtain intermediates 4 and 5;
(3) The mixture of the intermediates 4 and 5 is dissolved in a solvent, and chiral resolving agent is added for resolution to obtain an intermediate 5; the chiral resolving agent is selected from camphorsulfonic acid;
(4) Dissolving the intermediate 5 in a solvent, and adding thionyl chloride for ring opening to obtain an intermediate 6; the solvent is methanol;
(5) Adding a catalyst into the intermediate 6 for deprotection, and simultaneously reacting with Boc anhydride or Z-OSU to obtain a target product 7 or 8; the catalyst is selected from palladium carbon;
the specific synthetic route is as follows:
or (b)
。
2. The process for preparing a cis-D-hydroxyproline derivative according to claim 1, wherein the reaction temperature in the step (1) is 80 to 100 ℃ and the reaction time is 8 to 24 hours.
3. The process for producing a cis-D-hydroxyproline derivative according to claim 1, wherein in the step (1), the reaction molar ratio of the aromatic amine 1 to 3-bromopropene is 1 (1.1 to 1.50), the reaction molar ratio of the aromatic amine 1 to potassium carbonate is 1 (2.5 to 4.0), and the reaction molar ratio of the aromatic amine 1 to potassium iodide is 1 (0.5 to 1.0).
4. The process for producing a cis-D-hydroxyproline derivative according to claim 1, wherein in the step (2), the reaction molar ratio of the intermediate 3 to glyoxylate is 1 (1.1 to 1.5).
5. The process for producing a cis-D-hydroxyproline derivative according to claim 1, wherein in the step (2), the reaction temperature is 50 to 65 ℃ and the reaction time is 2 to 6 hours.
6. The process for preparing a cis-D-hydroxyproline derivative according to claim 1, wherein in the step (3), the molar ratio of the mixture of intermediates 4 and 5 to the chiral resolving agent is 0.8 to 1.2.
7. The process for producing a cis-D-hydroxyproline derivative according to claim 1, wherein in the step (4), the reaction molar ratio of the intermediate 5 to thionyl chloride is 1 (2.0 to 3.0).
8. The process for producing a cis-D-hydroxyproline derivative according to claim 1, wherein in the step (4), the reaction time is 8 to 16 hours and the reaction temperature is 50 to 65 ℃.
9. The process for producing a cis-D-hydroxyproline derivative according to claim 1, wherein in the step (5), the reaction time is 8 to 24 hours, the reaction temperature is 30 to 50 ℃, and the reaction pressure is 3 to 5Mpa.
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