CN114736151B - Preparation method of Pa Luo Weide key intermediate and structural formula of compound - Google Patents

Preparation method of Pa Luo Weide key intermediate and structural formula of compound Download PDF

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CN114736151B
CN114736151B CN202210389871.1A CN202210389871A CN114736151B CN 114736151 B CN114736151 B CN 114736151B CN 202210389871 A CN202210389871 A CN 202210389871A CN 114736151 B CN114736151 B CN 114736151B
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weide
luo
key intermediate
boc
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CN114736151A (en
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鲁光英
罗志希
苏位东
周跃辉
谭密
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Hunan Furui Biomedical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • 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 provides a preparation method of a key intermediate of Pa Luo Weide and a structural formula of a compound, wherein amino of L-serine is protected by BOC, and the amino reacts with trimethoxy phosphine to generate the compound 4; the compound 4 reacts with tert-butyl dimethyl siloxyacetaldehyde to obtain a compound 5 which is cyclopropanated with 2, 2-dichloropropane to obtain a compound 6; the hydroxy of the compound 7 obtained by desilication protection of the compound 6 is halogenated to obtain a compound 8, and the compound 8 is cyclized to obtain a compound 9, and then BOC protection is removed to obtain a compound 2 of a key intermediate of Pa Luo Weide. The invention takes cheap L-serine and tert-butyl dimethyl silicon protected hydroxy acetaldehyde as raw materials, and prepares the key intermediate of Pa Luo Weide through construction of Z-type double bond, cyclopropane and desilication base protection and final cyclization. The method has the advantages of simple operation, cheap raw materials and simple synthesis steps, effectively avoids the problems of double bond position isomerism and chiral racemization, and is suitable for industrial production.

Description

Preparation method of Pa Luo Weide key intermediate and structural formula of compound
Technical Field
The invention relates to the technical field of organic matter synthesis pharmacy, in particular to a preparation method of a key intermediate of Pa Luo Weide and a structural formula of a compound.
Background
Pampers Luo Weide (Paxlovid) are drugs developed by pyroxene for the treatment of new coronaries, which have been approved by various countries for marketing, and the main active ingredient structure is shown in compound 1.
Figure BDA0003595173080000011
In the synthesis process of the compound 1, the compound 2 (proline fragment of cyclopropyl) is a key intermediate thereof, and is also a key point of main synthesis technical difficulty and restriction of product cost control, and in the prior art, the synthesis method of the compound is as follows:
the method comprises the following steps: document synthosis (1982,753) uses chiral hydroxyproline as a raw material, methyl esterification is carried out, boc protection is carried out on amino, and then hydroxyl is made into a leaving group, such as iodine, sulfonyl, trifluoromethanesulfonyl and phenylseleno; and then eliminating double bond by alkali, and cyclopropanating to obtain the cyclopropyl proline. The method has long route, can generate position isomerism when eliminating the obtained double bond, and can generate chiral racemization when eliminating the trifluoro methylsulfonyl although the benzene seleno eliminates the position isomerism, wherein the selenium reagent is extremely toxic, and the formula is as follows:
Figure BDA0003595173080000021
the second method is as follows: the literature synthosis (2001,46) synthesizes Boc-dihydropyrrole first, then synthesizes racemic Boc-dihydropyrroline methyl ester, carries out enzymatic hydrolysis and resolution to obtain proline, and then carries out methyl esterification and cyclopropanation. The method has the defects that the synthesis of Boc-dihydropyrrole is not easy, half of isomers are not useful after chiral resolution, and carboxyl is subjected to methyl esterification again, wherein the formula is as follows:
Figure BDA0003595173080000022
and a third method: document Journal of Medicinal Chemistry (2006, 6074) starts from pyroglutamic acid and reduces carboxyl to hydroxyl groups, benzaldehyde protection, building up olefins, cyclopropylating, then reducing amides, protecting amino groups, oxidizing hydroxyl groups to carboxylic acids and esterifying. The route is long, and high-risk operations such as low temperature, lithium aluminum hydride and the like are adopted, and the following formula is adopted:
Figure BDA0003595173080000023
disclosure of Invention
Aiming at the defects and problems in the prior art, the invention provides a preparation method of a key intermediate of Pa Luo Weide and a structural formula of a compound.
In order to achieve the above purpose, the present invention provides the following technical solutions:
a process for the preparation of a key intermediate of pampers Luo Weide comprising the steps of:
step one, protecting amino of L-serine with BOC, and reacting with trimethoxy phosphine to generate a compound 4;
step two, reacting the compound 4 with tert-butyl dimethyl siloxyacetaldehyde to obtain a compound 5;
step three, cyclopropanation is carried out on the compound 5 and 2, 2-dichloropropane to obtain a compound 6;
step four, protecting the desilication group of the compound 6 to obtain a compound 7;
step five, halogenating the hydroxyl of the compound 7 to obtain a compound 8;
step six, cyclizing the compound 8 to obtain a compound 9;
step seven, compound 9 is deprotected by BOC to afford compound 2, a key intermediate to pampers Luo Weide.
In the technical scheme, the BOC protective agent comprises Boc-acetic anhydride, (Boc) 2 O。
In the technical scheme, the trimethoxyphosphine is replaced by triethoxyphosphine.
In the above technical scheme, in the third step, the compound 5 is cyclized with 2, 2-dichloropropane under the action of a zinc-copper coupling agent to obtain a compound 6.
In the above technical scheme, in the fourth step, tetrabutylammonium fluoride is used to remove the silicon-based protection in the compound 6.
In the above technical scheme, in the sixth step, the cyclization reaction manner of the compound 8 to the compound 9 is as follows: powdered sodium carbonate is added into anhydrous tetrahydrofuran to form a ring.
The invention also discloses a structural formula for synthesizing the compound 2, wherein the structural formula is as follows:
Figure BDA0003595173080000031
wherein: x is X 1 A group comprising a halogen group, and an amino group forming a ring; x is X 2 Is a chain hydrocarbon group; x is X 3 For protecting groups, structures for protecting amino groups.
In the above technical solution, the X 1 Included-OMs, -OTs, -Cl, -Br, -I, -OTf, the protecting group comprising BOC, FMOC, the chain hydrocarbon group comprising methyl, ethyl, propyl.
The invention takes cheap L-serine and tert-butyl dimethyl silicon protected hydroxy acetaldehyde as initial raw materials, and prepares key intermediate of Pa Luo Weide through construction of Z-type double bond, cyclopropane and desilication protection and final cyclization. The method has the advantages of simple operation, cheap raw materials and simple synthesis steps, effectively avoids the problems of double bond position isomerism and chiral racemization, and is suitable for industrial production.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. 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.
The preparation method of the key intermediate of Pa Luo Weide comprises the following steps:
step one, protecting amino of L-serine with BOC, and reacting with trimethoxy phosphine to generate a compound 4;
step two, reacting the compound 4 with tert-butyl dimethyl siloxyacetaldehyde to obtain a compound 5;
step three, cyclopropanation is carried out on the compound 5 and 2, 2-dichloropropane to obtain a compound 6;
step four, protecting the desilication group of the compound 6 to obtain a compound 7;
step five, halogenating the hydroxyl of the compound 7 to obtain a compound 8;
step six, cyclizing the compound 8 to obtain a compound 9;
step seven, compound 9 is deprotected by BOC to afford compound 2, a key intermediate to pampers Luo Weide.
The specific synthetic route is shown in the following formula:
Figure BDA0003595173080000051
specific example 1:
50g of serine, 100g of sodium carbonate and 300g of water are added, stirred at room temperature for dissolution and clarification, 115g of Boc anhydride is added dropwise, then stirred at room temperature for 24 hours, acetic acid is added for regulating the pH value to 6-7, then 300ml of ethyl acetate is added for extracting the product, the extraction is carried out twice, anhydrous sodium sulfate is dried, and the crude product 101.1g is obtained after concentration and drying.
101.1g of the crude product obtained in the above, 88.5g of trimethoxyphosphine and 274.5g of triphenylphosphine are added into 1000ml of tetrahydrofuran, stirred, dissolved and clarified, cooled to below-10 ℃, 182.3g of diethyl azodicarboxylate per 100ml of tetrahydrofuran solution is slowly added dropwise, the temperature is kept for 2 hours after the dropwise addition, and then the mixture is concentrated under reduced pressure and purified by a column to obtain 74.5g of compound 4.
11.2g of potassium tert-butoxide is dissolved in 300ml of anhydrous tetrahydrofuran, 31.1g of a solution of the compound 4 in 50ml of anhydrous tetrahydrofuran is slowly added dropwise under ice water bath, the temperature is controlled to be not more than 10 ℃, stirring is carried out for half an hour after adding, 17.4g of tert-butyldimethyl siloxyacetaldehyde in 50ml of anhydrous tetrahydrofuran is then added dropwise, the temperature is slowly increased to 25 ℃ after adding, stirring is carried out until TLC shows that the reaction is complete, the mixture is slowly poured into ice water, liquid separation and extraction by aqueous ethyl acetate are carried out, the organic phases are combined, drying and concentration are carried out, and 31.5g of the compound 5 is obtained through column chromatography.
3.2g of zinc-copper coupling agent, 17.9g of compound 5, 6.35g of zinc powder and 11.18g of zinc bromide are respectively added into 100ml of anhydrous tetrahydrofuran, after being stirred for half an hour at 25 ℃, 11.3g of 2, 2-dichloropropane is slowly added dropwise, after the addition, the mixture is stirred at 25 ℃ until the detection reaction is complete, ice water is added, the filtration and the separation are carried out, the aqueous phase ethyl acetate extraction are carried out, the organic phases are combined, the drying and the concentration are carried out, and 16.6g of compound 6 is obtained by column chromatography.
16g of Compound 6 was dissolved in 80ml of methylene chloride, 10.44g of tetrabutylammonium fluoride was added, stirred until the reaction was completed, the organic phase was washed with sodium hydrogencarbonate solution, dried and concentrated to dryness to obtain Compound 7, 100ml of tetrahydrofuran, 13.28g of carbon tetrabromide and 10.48g of triphenylphosphine were added, stirred until the starting materials disappeared, filtered, concentrated to dryness, and column chromatography was performed to obtain 12.8g of Compound 8.
12g of Compound 8 was dissolved in 50ml of anhydrous tetrahydrofuran, 13.8g of powdery potassium carbonate was added, stirred until the reaction was complete, filtered, and concentrated to give 8.5g of Compound 9.
8g of Compound 9 was dissolved in 50ml of anhydrous methanol, 6g of concentrated hydrochloric acid was added, stirred until the reaction was complete, filtered, and concentrated to dryness to give 6.8g of Compound 2.
Specific example 2:
serine 50g, sodium carbonate 100g, and water 300g were added, and the mixture was stirred at room temperature to clarify the mixture, followed by dropwise addition (Boc) 2 106g of O, stirring for 20 hours at room temperature, adding acetic acid to adjust the pH value to 6-7, adding 300ml of ethyl acetate to extract the product, extracting twice, drying by anhydrous sodium sulfate, and concentrating to obtain 100.4g of crude product. 100.4g of the crude product obtained in the above way, 88.1g of triethoxy phosphine and 272.3g of triphenylphosphine are added into 1000ml of tetrahydrofuran, stirred, dissolved and clarified, cooled to below-10 ℃, 181.1g of diethyl azodicarboxylate/100 ml of tetrahydrofuran solution is slowly added dropwise, the temperature is kept for 2 hours after the dropwise addition, and then the mixture is concentrated under reduced pressure and purified by a column to obtain 76.3.6g of solid.
Dissolving 20g of potassium tert-butoxide in 300ml of anhydrous tetrahydrofuran, slowly dropwise adding 36g of the solid solution in 50ml of anhydrous tetrahydrofuran under ice water bath, controlling the temperature to be not more than 10 ℃, stirring for half an hour after adding, then dropwise adding 19.6g of tert-butyldimethyl siloxyacetaldehyde in 50ml of anhydrous tetrahydrofuran, slowly heating to 25 ℃ after adding, stirring until TLC (thin layer chromatography) shows that the reaction is complete, slowly pouring into ice water, separating liquid, extracting by using ethyl acetate in water phase, combining organic phases, drying and concentrating, and obtaining 34.1g of compound 5 through column chromatography.
3.2g of zinc-copper coupling agent, 17.9g of compound 5, 6.35g of zinc powder and 11.18g of zinc bromide are respectively added into 100ml of anhydrous tetrahydrofuran, after being stirred for half an hour at 25 ℃, 11.3g of 2, 2-dichloropropane is slowly added dropwise, after the addition, the mixture is stirred at 25 ℃ until the detection reaction is complete, ice water is added, the filtration and the separation are carried out, the aqueous phase ethyl acetate extraction are carried out, the organic phases are combined, the drying and the concentration are carried out, and 16.6g of compound 6 is obtained by column chromatography.
16g of Compound 6 was dissolved in 80ml of methylene chloride, 10.44g of tetrabutylammonium fluoride was added, stirred until the reaction was completed, the organic phase was washed with sodium hydrogencarbonate solution, dried and concentrated to dryness to obtain Compound 7, 100ml of tetrahydrofuran, 13.28g of carbon tetrabromide and 10.48g of triphenylphosphine were added, stirred until the starting materials disappeared, filtered, concentrated to dryness, and column chromatography was performed to obtain 12.8g of Compound 8.
12g of Compound 8 was dissolved in 50ml of anhydrous tetrahydrofuran, 13.8g of powdery potassium carbonate was added, stirred until the reaction was complete, filtered, and concentrated to give 8.5g of Compound 9.
8g of Compound 9 was dissolved in 50ml of anhydrous methanol, 6g of concentrated hydrochloric acid was added, stirred until the reaction was complete, filtered, and concentrated to dryness to give 6.8g of Compound 2.
The invention also provides an intermediate structural formula for synthesizing the compound 2, which is shown as a compound 10, wherein X1 is a halogen group or other groups which can form a ring with amino, preferably-OMs, -OTs, -Cl, -Br, -I and-OTf; x2 is methyl, ethyl, propyl or other chain hydrocarbon groups; x3 is a protecting group, preferably BOC, FMOC, for protecting the structure of the amino group. Compound 10 can be prepared by a simple cyclization reaction to obtain compound 2, which is a key intermediate for synthesizing compound 2.
Figure BDA0003595173080000081
The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily recognize that variations or substitutions are within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (7)

1. A preparation method of a key intermediate of Pa Luo Weide is characterized by comprising the following steps: the method comprises the following steps:
step one, protecting amino of L-serine with BOC, and reacting with trimethoxy phosphine to generate a compound 4;
step two, reacting the compound 4 with tert-butyl dimethyl siloxyacetaldehyde to obtain a compound 5;
step three, cyclopropanation is carried out on the compound 5 and 2, 2-dichloropropane to obtain a compound 6;
step four, protecting the desilication group of the compound 6 to obtain a compound 7;
step five, halogenating the hydroxyl of the compound 7 to obtain a compound 8;
step six, cyclizing the compound 8 to obtain a compound 9;
step seven, removing BOC protection from the compound 9 to obtain a compound 2 of a key intermediate of Pa Luo Weide;
wherein the structural formulas of the compound 4, the compound 5, the compound 6, the compound 7, the compound 8, the compound 9 and the compound 2 are shown in the following figures:
Figure FDA0004066817810000011
2. the method for preparing the key intermediate of pampers Luo Weide according to claim 1, wherein the method comprises the following steps: in the first step, the BOC protective agent comprises Boc-acetic anhydride (Boc) 2 O。
3. A process for the preparation of a key intermediate of pa Luo Weide according to claim 1 or 2, characterized in that: in step one, the trimethoxyphosphine is replaced with triethoxyphosphine.
4. A process for the preparation of a key intermediate of pa Luo Weide as claimed in claim 3, wherein: in the third step, the compound 5 is cyclized with 2, 2-dichloropropane under the action of a zinc-copper coupling agent to obtain a compound 6.
5. The method for preparing the key intermediate of pampers Luo Weide, according to claim 4, wherein the method comprises the following steps: in the fourth step, tetrabutylammonium fluoride is used for removing the silicon-based protection in the compound 6.
6. The method for preparing the key intermediate of pampers Luo Weide, according to claim 5, wherein the method comprises the following steps: in the sixth step, the cyclization reaction mode of the compounds 8 to 9 is as follows: powdered sodium carbonate is added into anhydrous tetrahydrofuran to form a ring.
7. A compound of the formula, characterized by: a key intermediate for the synthesis of pampers Luo Weide as claimed in claims 1 to 6, said structural formula:
Figure FDA0004066817810000021
wherein: x is X 1 including-TBSO, -OMs, -OTs, -Cl, -Br, -I, -OTf; x is X 2 Including methyl, ethyl, propyl; x is X 3 Including BOC, FMOC. />
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Denomination of invention: A key intermediate preparation method for Parovide and structural formula of its compound

Granted publication date: 20230421

Pledgee: Agricultural Bank of China Xiangtan County Branch

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