CN113620855A - Yiwan kasai intermediate II and synthetic method thereof - Google Patents
Yiwan kasai intermediate II and synthetic method thereof Download PDFInfo
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- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims abstract description 17
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims abstract description 16
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- -1 alcohol compound Chemical class 0.000 claims abstract description 10
- CSEWAUGPAQPMDC-UHFFFAOYSA-N 2-(4-aminophenyl)acetic acid Chemical compound NC1=CC=C(CC(O)=O)C=C1 CSEWAUGPAQPMDC-UHFFFAOYSA-N 0.000 claims abstract description 8
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
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- 238000010438 heat treatment Methods 0.000 claims description 6
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- 238000002360 preparation method Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000000849 parathyroid Effects 0.000 description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- RZNUIYPHQFXBAN-XLIONFOSSA-N 2-[4-[(3s)-3-[[(1r)-1-naphthalen-1-ylethyl]amino]pyrrolidin-1-yl]phenyl]acetic acid Chemical compound C([C@@H](C1)N[C@H](C)C=2C3=CC=CC=C3C=CC=2)CN1C1=CC=C(CC(O)=O)C=C1 RZNUIYPHQFXBAN-XLIONFOSSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000005770 Secondary Hyperparathyroidism Diseases 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N benzyl-alpha-carboxylic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960000478 cinacalcet hydrochloride Drugs 0.000 description 1
- QANQWUQOEJZMLL-PKLMIRHRSA-N cinacalcet hydrochloride Chemical compound Cl.N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 QANQWUQOEJZMLL-PKLMIRHRSA-N 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
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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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/34—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 two 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/416—2,5-Pyrrolidine-diones 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 other ring carbon atoms
-
- 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
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention relates to the field of pharmaceutical chemistry synthesis, and in particular relates to an Yiwan kasai intermediate II and a synthesis method thereof. The synthesis method comprises the following steps: 4-aminophenylacetic acid and an alcohol compound are taken as initial raw materials, an esterifying agent is dripped into the initial raw materials, an intermediate I is prepared by decompression and concentration, then the intermediate I is dripped into an L-malic acid solution to be mixed and heated, and the intermediate I is subjected to decompression, concentration and recrystallization to obtain an Yiwanka intermediate II, wherein the alcohol compound is any one of methanol, ethanol, propanol and isopropanol, and the intermediate II has the following structural formula. The synthesis method provided by the invention has the advantages of safe conditions, cheap and easily available raw materials, good quality of the obtained avancin kasai intermediate II, high yield and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of synthesis of medicines and medicine intermediates, and particularly relates to an ivacaine kasai intermediate II and a synthesis method thereof.
Background
Avancil, a novel CaR agonist of arylalkyl amine compounds, having the chemical name (4- { (3S) -3- [ (1R) -1- (naphthalen-1-yl) ethylamino ] pyrrolidin-1-yl } phenyl) acetic acid [ 4- { (3S) -3- [ (1R) -1- (naphtalen-1-yl) ethyl lamino ] pyrrolidin-1-yl } phenyl acetic acid ], and having the chemical structure as follows.
Avancin plugs are used to treat secondary hyperparathyroidism in maintenance dialysis patients. It acts on Ca receptor on the surface of parathyroid cell, inhibits secretion of PTH, lowers the concentration of PTH in blood, and further relieves symptoms, and furthermore, avancin also regulates the biosynthesis of PTH and proliferation of parathyroid cell, controlling the production of PTH. Compared with the early calcium mimetic cinacalcet hydrochloride, avancin significantly reduced digestive tract disease.
Currently, there are few methods available to synthesize avanci jams. One of the synthetic routes is as follows:
for example, Hiroshi Miyazaki et al (Bioorganic & Medicinal Chemistry Letters 28 (2018)) 2055-.
The advantages and disadvantages of this route: the route can be used for industrial production, but 3-pyrrolidinol is used in the process and is expensive.
Therefore, the synthesis method of the intermediate of the avancin kazakh, which is low in cost, safe, environment-friendly, convenient to operate, high in yield, good in quality and suitable for industrial production, is provided by adopting the alcohol compound, the L-malic acid and the 4-aminophenylacetic acid as raw materials.
Disclosure of Invention
In view of the above, the invention aims to provide a synthesis method of the intermediate II of avancin kasai, which has the advantages of low cost, safety, environmental protection, convenient operation, good quality, high yield and suitability for industrial production. The method comprises the steps of taking 4-aminophenylacetic acid and any one of methanol, ethanol, propanol and isopropanol as starting raw materials, dropwise adding an esterifying agent, carrying out reduced pressure concentration to obtain an intermediate I, then adding the intermediate I into an L-malic acid solution, carrying out reduced pressure concentration and recrystallization to obtain an intermediate II. The synthesis method of the preparation method of the intermediate II of the avancin kazakh has mild conditions, cheap and easily available raw materials, high yield of the obtained product and suitability for mass production.
In order to achieve the purpose, the invention adopts the following technical scheme:
the Yiwan kasai intermediate II is characterized in that the structure simple formula is as follows:
a synthetic method of an avancin kasai intermediate II specifically comprises the following steps:
mixing L-malic acid and an organic solvent A, heating to 70-200 ℃, adding an intermediate I and the organic solvent A, refluxing for 5-15h at the temperature of 100 ℃ and 130 ℃, concentrating, evaporating to dryness, adding an organic solvent B for dissolving, concentrating until no liquid is evaporated to obtain brown viscous liquid, adding the organic solvent B, heating for dissolving, magnetically stirring for crystallization, performing suction filtration to obtain a light yellow solid, and finally adding the organic solvent B for recrystallization to obtain a pure white crystal intermediate II (S) -2- (4- (3-hydroxy-2, 5-dioxapyrrolidine-1-yl) phenyl) acetate compound;
the structure of the intermediate I is shown as the simple formula
Wherein R is-CH3、-CH2CH3、-CH(CH3)2and-CH2CH2CH3Any one of the above.
Preferably, the molar ratio of the intermediate I to the L-malic acid is 1: (1.0-1.2).
Preferably, the organic solvent a is any one of toluene, xylene, tetrahydrofuran and acetonitrile; the organic solvent B is any one of methanol, absolute ethyl alcohol and acetonitrile.
Preferably, the preparation steps of the intermediate I are as follows: magnetically stirring 4-aminophenylacetic acid and an alcohol compound in an ice water bath until the temperature is 0-8 ℃, then slowly dropwise adding an esterifying agent, refluxing for 3-8h at 65-98 ℃ after dropwise adding, concentrating under reduced pressure until no liquid is evaporated out to obtain a light yellow oily substance, adding n-hexane, generating a solid, performing suction filtration to obtain a gray solid, adding ethyl acetate into the gray solid, sequentially dropwise adding triethylamine and water under magnetic stirring, performing liquid separation, washing with water, and finally concentrating under reduced pressure to obtain a brown liquid intermediate I;
the alcohol compound is any one of methanol, ethanol, propanol and isopropanol.
Preferably, the molar ratio of the 4-aminophenylacetic acid, the alcohol compound and the esterifying agent is 1: (5-20): (1-3).
Preferably, the esterifying agent is any one of thionyl chloride, sulfuric acid and hydrochloric acid.
The overall reaction flow for preparing the intermediate II and the Yiwan kasai is as follows:
wherein R is-CH3、-CH2CH3、-CH(CH3)2and-CH2CH2CH3Any one of the above.
Through the technical scheme, compared with the prior art, the invention discloses a synthetic method of an avancin kasai intermediate. The method has the following technical effects:
1. the raw materials are cheap and easy to obtain, and the preparation method is safe and environment-friendly.
2. The yield of the finally prepared avancin kasai intermediate is high, the quality is good, and the method is suitable for large-scale production.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.
FIG. 1 shows a hydrogen spectrum of intermediate II in the example of the present invention.
FIG. 2 is a carbon spectrum of intermediate II in the example of the present invention.
FIG. 3 is an enlarged view of the carbon spectrum of intermediate II in the example of the present invention.
FIG. 4 is a mass spectrum of intermediate II in the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. 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.
Examples
(1) Preparation of intermediate I
5.05g of 4-aminophenylacetic acid and 25mL of methanol are added into a 500mL three-necked flask, the mixture is stirred by magnetic force in an ice water bath, and 2.5mL of thionyl chloride starts to be slowly dropped at 5 ℃. After the dripping is finished, refluxing is carried out for 6h at 65 ℃, and decompression concentration is carried out at 45 ℃ until no liquid is evaporated out, thus obtaining light yellow oily matter. Adding 50mL of n-hexane to generate solid, performing suction filtration to obtain 6.75g of gray solid, transferring the gray solid into a 250mL three-necked bottle, adding 50mL of ethyl acetate, dropwise adding 5mL of triethylamine under magnetic stirring, adding 30mL of water, separating, washing with 30mL of water for three times each time, and concentrating under reduced pressure to obtain 5.12g of brown liquid, namely the intermediate I4-methyl aminophenylacetate with the yield of 92.57%.
(2) Preparation of intermediate II
Adding 3.10g of L-malic acid and 40mL of dimethylbenzene into a 250mL three-necked bottle, heating to 80 ℃, adding 3.46g of intermediate I and 10mL of dimethylbenzene, refluxing for 12h, concentrating under reduced pressure, evaporating to dryness, adding 60mL of acetonitrile, concentrating under reduced pressure after complete dissolution until no liquid is evaporated to obtain brown viscous liquid, adding 20mL of organic solvent B, heating to completely dissolve the intermediate, magnetically stirring for crystallization, performing suction filtration to obtain light yellow solid, and recrystallizing with acetonitrile to obtain 2.63g of white solid, namely intermediate II (methyl (S) -2- (4- (3-hydroxy-2, 5-dioxapyrrolidine-1-yl) phenyl) acetate, wherein the yield is 50.01%.
The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (7)
1. The Yiwan kasai intermediate II is characterized in that the structure simple formula is as follows:
R＝CH3，CH3CH2，CH3CH3CH，CH3CH2CH2。
2. a synthetic method of an avancin kasai intermediate II is characterized by comprising the following steps:
mixing L-malic acid and an organic solvent A, heating to 70-200 ℃, adding an intermediate I and the organic solvent A, refluxing at 100-130 ℃ for 5-15h, concentrating, evaporating to dryness, adding an organic solvent B for dissolving and concentrating, adding the organic solvent B, heating for dissolving, stirring for crystallization, performing suction filtration, and finally adding the organic solvent B for recrystallization to obtain an intermediate II;
the structure of the intermediate I is shown as the simple formula
Wherein R is-CH3、-CH2CH3、-CH(CH3)2and-CH2CH2CH3Any one of the above.
3. The method for synthesizing the ivacaic kazakh intermediate II according to claim 2, wherein the molar ratio of the intermediate I to the L-malic acid is 1: (1.0-1.2).
4. The method for synthesizing the ivacaide intermediate II according to claim 2, wherein the organic solvent A is any one of toluene, xylene, tetrahydrofuran and acetonitrile;
the organic solvent B is any one of methanol, absolute ethyl alcohol and acetonitrile.
5. The method for synthesizing the itavanckazabete intermediate II according to claim 2, wherein the specific preparation steps of the intermediate I are as follows:
stirring 4-aminophenylacetic acid and an alcohol compound in an ice-water bath until the temperature is 0-8 ℃, then dropwise adding an esterifying agent, refluxing for 3-8h at 65-98 ℃ after the dropwise adding is finished, concentrating, adding n-hexane, performing suction filtration, sequentially adding triethylamine and water into the obtained gray solid and ethyl acetate under mixing and stirring, then performing liquid separation and water washing, and finally concentrating to obtain the intermediate I;
the alcohol compound is any one of methanol, ethanol, propanol and isopropanol.
6. The method for synthesizing itavancomycin intermediate II according to claim 5, wherein the molar ratio of the 4-aminophenylacetic acid, the alcohol compound and the esterifying agent is 1:
(5-20)：(1-3)。
7. the method for synthesizing the ivacaide intermediate II according to claim 5, wherein the esterifying agent is any one of thionyl chloride, sulfuric acid and hydrochloric acid.
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| CN111704577A (en) * | 2020-06-22 | 2020-09-25 | 华北水利水电大学 | Preparation method of cinacalcet hydrochloride |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117417285A (en) * | 2023-02-16 | 2024-01-19 | 苏中药业集团股份有限公司 | Isomanka key intermediate and preparation method thereof |
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