CN116120163B - Synthesis method of bevacizidine acid and intermediate thereof - Google Patents

Synthesis method of bevacizidine acid and intermediate thereof Download PDF

Info

Publication number
CN116120163B
CN116120163B CN202211742714.0A CN202211742714A CN116120163B CN 116120163 B CN116120163 B CN 116120163B CN 202211742714 A CN202211742714 A CN 202211742714A CN 116120163 B CN116120163 B CN 116120163B
Authority
CN
China
Prior art keywords
compound
bevacizidine
reaction
synthesizing
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202211742714.0A
Other languages
Chinese (zh)
Other versions
CN116120163A (en
Inventor
陈磊
陆平波
王晓宇
杨津敏
张晓伟
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Anhui Ailide Pharmaceutical Co ltd
Original Assignee
Anhui Ailide Pharmaceutical Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Anhui Ailide Pharmaceutical Co ltd filed Critical Anhui Ailide Pharmaceutical Co ltd
Priority to CN202211742714.0A priority Critical patent/CN116120163B/en
Publication of CN116120163A publication Critical patent/CN116120163A/en
Application granted granted Critical
Publication of CN116120163B publication Critical patent/CN116120163B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a novel intermediate compound of bevacizidine acid, and also discloses a synthesis method of the bevacizidine acid, which shortens route steps, reduces process cost, improves purity and yield of a final product, and is suitable for large-scale production.

Description

Synthesis method of bevacizidine acid and intermediate thereof
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a synthesis method of bevacizidine and an intermediate thereof.
Background
Bevacizidine is an oral adenosine triphosphate citrate lyase (ACL) inhibitor developed and marketed by Ai Sibai len treatment (Esperion Therapeutics) that reduces low-density lipoprotein cholesterol (LDL-C) by inhibiting cholesterol synthesis in the liver. The drug is marketed by FDA in month 2 2020 and can be used as an auxiliary drug for dietetic and maximum tolerating statin drugs for treating heterozygous familial hypercholesterolemia or established adult atherosclerosis cardiovascular diseases, and further cholesterol (LDL-C) reduction is required.
The chemical name of bevacizidine acid is 8-hydroxy-2,2,14,14-tetramethyl pentadecanedioic acid.
Esperion Therapeutics, international patent WO2004067489, specifications 6.19 and 6.20, disclose the earliest synthesis of bevacizidine, which requires distillation under reduced pressure for the first purification step and the boiling point of the product is very high (over 230 ℃); the second step of purification needs column chromatography, which is not beneficial to industrial production, and the purity of the obtained final product is low (83.8%) and the yield is low (60%); in addition, the synthesis route is long as a whole, the key raw material p-toluenesulfonyl methyl isonitrile belongs to an unusual raw material which is difficult to obtain, partial reaction is required to be carried out in low-temperature, anhydrous and anaerobic environments, more intermediate byproducts are difficult to clear, the purity of a final product is influenced, the process operation is complex, the production cost of the product is high, and the three wastes are more, so that the method is not suitable for scale-up production.
On the basis, CN201711044728.4 discloses a method for preparing bevacizidine acid by taking 8-keto-2,2,14,14-tetramethyl-pentadecanedioic acid as raw material; CN202010399519.7 discloses a method for synthesizing bevacizidine acid by using 3-bromo-2, 2-dimethylpropionic acid methyl ester and duplex pinacol boric acid ester as raw materials; CN202010665264.4 discloses a process for the synthesis of bevacizidine starting from 2, 5-dibromopentane; CN202011389141.9 discloses a process for the preparation of the intermediate 8-isocyanic acid-2,2,14,14-tetramethyl-8-p-acetylpentadiene diester and bexapric acid; CN202110060444.4 discloses, among other things, a process for synthesizing bevacizidine acid from ethyl isobutyrate and 1, 5-dibromopentane as starting materials. The synthetic methods in the patent documents provide new synthetic ideas and preparation methods from different angles, but the routes still have certain defects in the large-scale production, the byproducts of intermediates are more, the yield of the finished product of the bevacizidine is low, the post-treatment has certain danger and the three wastes are more, and the green synthetic routes of the bevacizidine with low cost, high efficiency and high yield still need to be continuously researched, which is very important for the economic and technical development of the raw material medicines of the bevacizidine.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a synthesis method of bevacizidine acid, which has the advantages of simple process route, low cost, high yield, less pollution discharge and suitability for industrial production.
The invention aims at providing a synthesis method of bevacizidine acid, which adopts the following scheme:
(1) Adding a substitution reaction solvent, an alkali accelerator, ethyl isobutyrate and 5-bromo-1-pentene into a reaction vessel, and carrying out substitution reaction under nitrogen and low temperature to obtain a compound 1-2;
(2) Then carrying out oxidation reaction under the action of a metal catalyst to obtain an intermediate compound 1-3;
(3) Adding a substitution reaction solvent, an alkali accelerator, ethyl isobutyrate and 1, 6-dibromohexane into a reaction container, and carrying out substitution reaction under nitrogen and low temperature to obtain a compound 2-2;
(4) Reacting the compound 2-2 under the action of phosphate and toluene or tetrahydrofuran to obtain an intermediate compound 2-3;
(5) Adding an alkali accelerator, a condensation solvent and a compound 1-3 into the compound 2-3, and reacting under nitrogen and room temperature to obtain a compound 3;
(6) Dissolving the compound 3 in tetrahydrofuran, dropwise adding dimethyl sulfide borane, and carrying out an addition reaction in an alkaline reagent to obtain a compound 4;
(7) Dissolving the compound 4 in ethanol, adding an alkaline reagent, and carrying out a reaction reflux reaction to obtain the bevacizidine acid, namely the compound 5.
The route is as follows:
the second purpose of the invention is to provide a synthesis method of bevacizidine acid, which adopts the following scheme:
Dissolving the compound 3 in tetrahydrofuran, dropwise adding dimethyl sulfide borane, and carrying out addition reaction in an alkaline reagent to obtain a compound 4; dissolving the compound 4 in ethanol, adding an alkaline reagent, and carrying out a reaction reflux reaction to obtain the bevacizidine acid, namely the compound 5:
As a preferable technical scheme, the feeding mole ratio of the ethyl isobutyrate, the 5-bromo-1-pentene and the alkali accelerator in the step (1) is 1:0.9-1:1.
As a preferable technical scheme, the feeding mole ratio of the ethyl isobutyrate, the 1, 6-dibromohexane and the alkali accelerator in the step (3) is 1:1-2:1.
As a preferred technical scheme, the alkali promoter is sodium hydride, phenyl lithium, n-butyl lithium, tert-butyl lithium, lithium diisopropylamide or lithium hexamethyldisilazide, preferably lithium diisopropylamide.
As a preferable technical scheme, the substitution reaction solvent is toluene, xylene, dimethyl sulfoxide, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile, preferably tetrahydrofuran.
As a preferable technical scheme, the reaction temperature of the substitution reaction in the step (1) is-30 to-40 ℃; the phosphate is selected from trimethyl phosphite, triethyl phosphite, triphenyl phosphite, preferably triethyl phosphite.
Preferably, the metal catalyst is selected from palladium on carbon, platinum on carbon, palladium hydroxide on carbon or palladium chloride, preferably palladium on carbon.
Preferably, the alkaline agent is selected from sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, and calcium hydroxide, preferably sodium hydroxide.
The invention also provides two kinds of bevacizidine intermediate compounds, which have the following structural formula:
Through the technical scheme, compared with the prior art, the invention has the following beneficial effects: the invention shortens the route steps, reduces the process cost, improves the structure of the bevacizidine acid intermediates, improves the crystallization performance of the bevacizidine acid intermediates, is beneficial to improving the purity and the yield of the final product, and is suitable for large-scale production.
Detailed Description
The following describes in detail the examples of the present invention, which are implemented on the premise of the technical solution of the present invention, and detailed embodiments and specific operation procedures are given, but the scope of protection of the present invention is not limited to the following examples.
Example 1:
(1) Preparation of Compounds 1-2
Tetrahydrofuran (700 mL) and lithium diisopropylamide (2.0M, 300mL,0.6 mol) are added into a 2L reaction vessel in sequence under the protection of nitrogen, and the temperature is reduced to-30 to-40 ℃ under stirring. After reaching the temperature, ethyl isobutyrate (70 g,0.6 mol) is added dropwise at the temperature of minus 30 to minus 40 ℃ and the reaction is carried out for 1 hour after the addition. 5-bromo-1-pentene (84.9 g,0.57 mol) was added dropwise and reacted overnight at 0-10 ℃. After the reaction was completed, the reaction was quenched with 2N HCl (400 mL), stirred for 30 minutes, and then allowed to stand for delamination. The aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined and washed with 5% NaHCO 3 (300 mL) and saturated brine (300 mL), respectively. The solution was dried over anhydrous sodium sulfate and concentrated in vacuo, and purified by chromatography to give Compound 1-2 as a pale yellow oil, 93.5g, 98.5% purity, 89% yield, HRMS (ESI): M/z [ M+H ] +: 185.28.
(2) Preparation of Compounds 1-3
Compound 1-2 (93.5 g,0.51 mol) was added to a 2L reaction vessel containing tetrahydrofuran (500 mL) and water (125 mL), 10% Pb/C (18 g) and KBrO 3 (255.5 g,1.53 mol) were further added, heated to reflux, the reaction was monitored by TLC, after the reaction was completed, 500mL of water was added for dilution, filtration was performed, the filtrate was extracted with ethyl acetate (200 mL. Times.3), the organic phases were combined, and then purified by column chromatography to give 85.8g of Compound 1-3 in 98.6% purity, yield 84%, HRMS (ESI): M/z [ M+H ] +: 201.28.
(3) Preparation of Compound 2-2
Tetrahydrofuran (1L) and lithium diisopropylamide (2.0M, 430mL,0.86 mol) are sequentially added into a 3L reaction vessel under the protection of nitrogen, and the temperature is reduced to-30 to-40 ℃ under stirring. After reaching the temperature, ethyl isobutyrate (100 g,0.86 mol) is added dropwise at the temperature of minus 30 to minus 40 ℃ and the reaction is carried out for 1 hour after the addition. 1, 6-dibromohexane (331.6 g,1.36 mol) was added dropwise, and the mixture was reacted overnight at 0 to 10 ℃. After the completion of the reaction, the reaction was quenched with 2 mol/L HCl (600 mL), stirred for 30 minutes, and then allowed to stand for delamination. The aqueous phase was extracted with ethyl acetate (300 ml x 3). The organic phases were combined and washed with 5% NaHCO 3 (500 mL) and saturated brine (500 mL), respectively. The solution was dried over anhydrous sodium sulfate and concentrated in vacuo, and the residue was distilled under high vacuum under reduced pressure to give compound 2-2 as a pale yellow oil, 180.1g, yield 75%, purity 99.2%, HRMS (ESI): M/z [ M+H ] +: 280.20.
(4) Preparation of Compounds 2-3
Compound 2-2 (134.5 g,0.48 mol), triethyl phosphite (87.7 g,0.53 mol) and toluene (600 mL) were added to a 2L reaction vessel, heated to reflux overnight, and after the reaction was completed, concentrated under reduced pressure until no flow was obtained to obtain compound 2-3, which was used directly in the next step without purification, in a yield of 100%, purity of 99.2%, HRMS (ESI): M/z [ m+h ] +: 337.41.
(5) Preparation of Compound 3
Compounds 2-3 (145 g,0.43 mol) were added to a suspension of sodium hydride (17.2 g,0.43 mol) in tetrahydrofuran (800 mL) under nitrogen over 20 minutes and the mixture stirred at room temperature until gas evolution ceased (about 30 minutes). Compounds 1 to 3 (77.6 g,0.39 mol) were added in portions and reacted at room temperature for 24H, after the reaction was completed, the reaction was quenched with water, the aqueous phase was extracted with ethyl acetate (500 mL. Times.3), and the organic phase was washed with saturated brine and purified by column chromatography to give 146.2g of Compound 3, purity 99.6%, yield 98%, HRMS (ESI): M/z [ M+H ] +: 383.61.
(6) Preparation of Compound 4
Compound 3 (146.2 g,0.38 mol) was dissolved in tetrahydrofuran (800 mL) at 0deg.C, and dimethyl sulfide borane was added dropwise to tetrahydrofuran (2M, 230mL,0.46 mol). After the addition was completed, stirring was carried out at room temperature overnight, then cooling to 0℃again, methanol (230 mL) was added dropwise, followed by aqueous NaOH (3N, 135mL,0.4 mol) and aqueous H 2O2 (30%, 135 mL). The resulting mixture was stirred at 60 ℃ for 1.5 hours, cooled to room temperature, added water (800 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic phases were washed with saturated brine (800 mL), dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure to give an orange oil, methyl tert-butyl ether (200 mL) was added, heated to dissolve, n-heptane (800 mL) was added, after addition was cooled to room temperature and stirred for 2 hours, filtered and dried to give 140g of compound 4, purity 99.3%, yield 92％.1H NMR(400MHz,CDCl3):δ4.08(q,4H),δ3.60(m,1H),δ1.51(m,4H),δ1.43(m,6H),δ1.28(m,16H),δ1.14(s,12H).
(7) Preparation of Compound 5
Compound 4 (140 g,0.35 mol) was dissolved in ethanol (700 mL), aqueous NaOH (42 g,1.05 mol) was added at room temperature, and after the addition, the reaction was warmed to reflux for 4 hours, cooled to room temperature, concentrated to remove ethanol, water (200 mL) was added, and extracted twice with dichloromethane (200 mL). The aqueous phase was adjusted to pH 1 with concentrated hydrochloric acid (130 mL) and extracted three times with methyl tert-butyl ether (200 mL). The organic phases were combined and concentrated to dryness under reduced pressure. N-heptane (700 mL) is added, heated to 50-60 ℃, stirred for 0.5 hour at a temperature of between 15 and 25 ℃ and stirred overnight. Suction filtration, rinsing with a suitable amount of n-heptane, and air drying the filter cake at 45℃until constant weight gave 114.3g of Compound 5, 99.8% pure, 95% yield, 1 H NMR (400 MHz, CDCl 3) δ3.58 (m, 1H), δ1.53 (m, 4H), δ1.38 (m, 16H), δ1.18 (d, 12H).
It will be understood by those skilled in the art that, unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the prior art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
The meaning of "and/or" in the present application means that each exists alone or both exist.
With the above-described preferred embodiments according to the present invention as an illustration, the above-described descriptions can be used by persons skilled in the relevant art to make various changes and modifications without departing from the scope of the technical idea of the present invention. The technical scope of the present invention is not limited to the description, but must be determined according to the scope of claims.

Claims (14)

1. The synthesis method of the bevacizidine acid is characterized by comprising the following steps of:
(1) Adding a substitution reaction solvent, an alkali accelerator, ethyl isobutyrate and 5-bromo-1-pentene into a reaction vessel, and carrying out substitution reaction under nitrogen and low temperature to obtain a compound 1-2;
(2) Then carrying out oxidation reaction under the action of a metal catalyst to obtain an intermediate compound 1-3;
(3) Adding a substitution reaction solvent, an alkali accelerator, ethyl isobutyrate and 1, 6-dibromohexane into a reaction container, and carrying out substitution reaction under nitrogen and low temperature to obtain a compound 2-2;
(4) Reacting the compound 2-2 under the action of triethyl phosphite and toluene or tetrahydrofuran to obtain an intermediate compound 2-3;
(5) Adding an alkali accelerator, a condensation solvent and a compound 1-3 into the compound 2-3, and reacting under nitrogen and room temperature to obtain a compound 3;
(6) Dissolving the compound 3 in tetrahydrofuran, dropwise adding dimethyl sulfide borane, and carrying out an addition reaction in an alkaline reagent to obtain a compound 4;
(7) Dissolving the compound 4 in ethanol, adding an alkaline reagent, and carrying out a reaction reflux reaction to obtain the bevacizidine acid, namely the compound 5; the route is as follows:
2. The synthesis method of the bevacizidine acid is characterized by comprising the steps of dissolving a compound 3 in tetrahydrofuran, dropwise adding dimethyl sulfide borane, and carrying out addition reaction in an alkaline reagent to obtain a compound 4; dissolving the compound 4 in ethanol, adding an alkaline reagent, and carrying out a reaction reflux reaction to obtain the bevacizidine acid, namely the compound 5:
3. The method for synthesizing bevacizidine acid according to claim 1, wherein: the feeding mole ratio of the ethyl isobutyrate, the 5-bromo-1-pentene and the alkali accelerator in the step (1) is 1:0.9-1:1.
4. The method for synthesizing bevacizidine acid according to claim 1, wherein: the feeding mole ratio of the ethyl isobutyrate, the 1, 6-dibromohexane and the alkali accelerator in the step (3) is 1:1-2:1.
5. The method for synthesizing bevacizidine acid according to claim 1, wherein: the alkali accelerator is sodium hydride, phenyl lithium, n-butyl lithium, tertiary butyl lithium, lithium diisopropylamide or lithium hexamethyldisilazide.
6. The method for synthesizing bevacizidine according to claim 5, wherein: the alkali accelerator is lithium diisopropylamide.
7. The method for synthesizing bevacizidine acid according to claim 1, wherein: the substitution reaction solvent is toluene, xylene, dimethyl sulfoxide, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile.
8. The method for synthesizing bevacizidine according to claim 7, wherein: the substitution reaction solvent is tetrahydrofuran.
9. The method for synthesizing bevacizidine acid according to claim 1, wherein: the reaction temperature of the substitution reaction in the step (1) is-30 to-40 ℃.
10. The method for synthesizing bevacizidine acid according to claim 1, wherein: the metal catalyst is selected from palladium on carbon, platinum on carbon, palladium hydroxide on carbon or palladium chloride.
11. The method for synthesizing bevacizidine acid according to claim 1, wherein: the metal catalyst is selected from palladium on carbon.
12. The synthesis method of bevacizidine acid according to claim 1 or 2, wherein: the alkaline reagent is selected from sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate and calcium hydroxide.
13. The method for synthesizing bevacizidine acid according to claim 12, wherein: the alkaline reagent is selected from sodium hydroxide.
14. A compound of the following formula (1-3), (2-3), characterized by the following structural formula:
CN202211742714.0A 2022-12-30 2022-12-30 Synthesis method of bevacizidine acid and intermediate thereof Active CN116120163B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202211742714.0A CN116120163B (en) 2022-12-30 2022-12-30 Synthesis method of bevacizidine acid and intermediate thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202211742714.0A CN116120163B (en) 2022-12-30 2022-12-30 Synthesis method of bevacizidine acid and intermediate thereof

Publications (2)

Publication Number Publication Date
CN116120163A CN116120163A (en) 2023-05-16
CN116120163B true CN116120163B (en) 2024-05-28

Family

ID=86300367

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202211742714.0A Active CN116120163B (en) 2022-12-30 2022-12-30 Synthesis method of bevacizidine acid and intermediate thereof

Country Status (1)

Country Link
CN (1) CN116120163B (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004067489A2 (en) * 2003-01-23 2004-08-12 Esperion Therapeutics, Inc. Hydroxyl compounds and compositions for cholesterol management and related uses
CN112479856A (en) * 2021-01-18 2021-03-12 南京工业大学 Synthesis method of piparidic acid
CN113233975A (en) * 2021-04-07 2021-08-10 海化生命(厦门)科技有限公司 Preparation method of biparidic acid
CN115108904A (en) * 2021-03-20 2022-09-27 上海鼎雅药物化学科技有限公司 Synthesis method of betimeric acid bulk drug

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004067489A2 (en) * 2003-01-23 2004-08-12 Esperion Therapeutics, Inc. Hydroxyl compounds and compositions for cholesterol management and related uses
CN112479856A (en) * 2021-01-18 2021-03-12 南京工业大学 Synthesis method of piparidic acid
CN115108904A (en) * 2021-03-20 2022-09-27 上海鼎雅药物化学科技有限公司 Synthesis method of betimeric acid bulk drug
CN113233975A (en) * 2021-04-07 2021-08-10 海化生命(厦门)科技有限公司 Preparation method of biparidic acid

Also Published As

Publication number Publication date
CN116120163A (en) 2023-05-16

Similar Documents

Publication Publication Date Title
CN111848607B (en) Novel BCL-2/BCL-XL inhibitor, pharmaceutical composition and application
KR100712003B1 (en) A process for producing phenserine and its analog
CN109096122B (en) Process for preparing spermidine
CN116120163B (en) Synthesis method of bevacizidine acid and intermediate thereof
CN109535120B (en) Preparation method of 7-substituted-3, 4,4, 7-tetrahydrocyclobutane coumarin-5-ketone
CN115124466B (en) Synthesis method of tetrahydropapaverine hydrochloride
CN111646964A (en) Novel method for synthesizing 2H-pyran-2-one derivative by base catalysis
CN112898152B (en) Preparation method of ethoxy diethyl methylene malonate
WO2021242807A1 (en) Methods for preparing methyl (s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionate and hydrochloric acid salts thereof
CN108727214B (en) Synthetic method of anesthetic bupivacaine impurity
CN101805380B (en) Method for preparing (3S, 5S)-2, 3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate
CN111777554A (en) Method for synthesizing cisatracurium besilate
CN111217709A (en) Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride
CN103848756B (en) Preparation method of teriflunomide and intermediate thereof
US6720463B1 (en) Process for the production of alkanediol derivative
CN115322106B (en) Synthesis method of trans-3-azido-1-methylcyclobutanol and trans-3-amino-1-methylcyclobutanol
CN112094257B (en) Preparation method of delta-9 tetrahydrocannabinol
KR101778345B1 (en) Preparation of 3,5-dioxo hexanoate ester in two steps
JPH01207266A (en) Production of 3-hydroxypyrrolidine or derivative thereof
CN117623923A (en) Synthesis method of bevacizidine acid intermediate compound
CN110804021A (en) Synthesis method of 2-aryl-4-aminoquinazoline
CN118290456A (en) Preparation method of difluoro oxalic acid borate
CN116836141A (en) New bevacizidine intermediate, preparation method thereof and method for synthesizing bevacizidine by using same
CN1283177A (en) Process for the preparation of isopropyl-methyl-[2-(3-N-Propoxyphenoxy) ethyl] amine
CN111606808A (en) Synthetic method of 3 ', 4', 5 '-trifluoro-2-nitro-1, 1' -biphenyl

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant