CN111848505B - Vardutasteride Process for the preparation of intermediates - Google Patents

Vardutasteride Process for the preparation of intermediates Download PDF

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CN111848505B
CN111848505B CN201910341763.5A CN201910341763A CN111848505B CN 111848505 B CN111848505 B CN 111848505B CN 201910341763 A CN201910341763 A CN 201910341763A CN 111848505 B CN111848505 B CN 111848505B
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compound
reaction
vad05
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vad07
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CN111848505A (en
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肖清波
林碧悦
寇景平
孙景伟
丘鑫福
王仲清
罗忠华
黄芳芳
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a preparation method of a vallisamisole intermediate, belonging to the field of pharmaceutical chemistry. The preparation method comprises the steps of taking 3-methoxy-5- (3-chlorophenyl) -2-cyanopyridine as a starting material, performing hydrolysis reaction, and performing condensation reaction to obtain a compound, namely the intermediate; the intermediate compound can be further reacted to obtain vadadustat (vallisat); the method has the advantages of short route, simple and easily obtained raw materials, lower cost and milder reaction conditions, and is suitable for industrial scale-up production.

Description

Vardutasteride Process for the preparation of intermediates
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of a vallisamisole intermediate.
Background
Vadadurat (vardutaster) is an oral Hypoxia Inducible Factor (HIF) stabilizer and is currently used in phase 3 clinical trials to treat anemia associated with chronic kidney disease. The chemical name is N- (5- (3-chlorophenyl) -3-hydroxypyridine-2-carbonyl) glycine, and the chemical structural formula is as follows:
the Vadadurat synthesis route disclosed in U.S. Pat. No. 3, 20070299086, taken in 7 steps, had a total yield of 9%.
The route is longer and the yield is lower. The first step of benzyl substitution reaction has harsh conditions and cannot be amplified, and in addition, the first step of hydrogenation reaction and the first step of coupling reaction are inconvenient to operate, have high cost and are not suitable for amplification.
A synthetic route for the preparation of Vadadurat is disclosed in U.S. Pat. No. 3, 20120309977: taking 3-chlorobenzoic acid and 3, 5-dichloro-2-cyanopyridine as starting materials, obtaining Vadadurat through catalytic coupling, methoxy substitution, cyano hydrolysis, condensation and ester hydrolysis reaction, carrying out 5 steps of reaction,
In the route, strong acid reaction and strong alkali reaction are carried out, and the reaction environment has higher requirements on a reaction container.
Therefore, the preparation method of Vadadurat and the intermediate thereof still needs to be studied to obtain the preparation method which has the advantages of simple operation, easy implementation, high yield, high purity, low cost and environmental friendliness and is suitable for industrial scale-up production.
Disclosure of Invention
The invention provides a preparation method of a valdostat intermediate, which has a structure shown as a formula R4-VAD 07:
The preparation method of the invention can take 3-methoxy-5- (3-chlorophenyl) -2-cyanopyridine (compound VADB-004) as a starting material, obtain 5- (3-chlorophenyl) -3-methoxy-2-picolinic acid (compound R4-VAD 05) through hydrolysis reaction, and obtain N- (5- (3-chlorophenyl) -3-methoxypyridine-2-carbonyl) glycine (compound R4-VAD 07) through condensation reaction. Compound R4-VAD07 can be further reacted to give vadadustat (vardostat). The specific reaction route is as follows:
in one aspect, the invention provides a method for preparing a valdostat intermediate compound R4-VAD07,
The method comprises the steps of reacting a compound R4-VAD05 with glycine or a salt thereof in a reaction solvent in the presence of a condensing agent and alkali, and performing post-treatment to obtain the compound R4-VAD07. The method for preparing the intermediate R4-VAD07 does not need to use nitrogen protection, and has mild reaction conditions and high yield.
In some embodiments, the condensing agent is selected from at least one of CDI, EDCI, DCC and PyBOP. In some embodiments, the condensing agent is CDI.
In some embodiments, the base is an organic base or an inorganic base.
In some embodiments, the base is selected from at least one of DIPEA, TEA, DMAP, DABCO and NaHCO 3. In some embodiments, the base is DIPEA or TEA.
In some embodiments, the reaction solvent is an organic solvent, which may be selected from at least one of DMSO, DMF, DMAC, DCM and THF. In some embodiments, the reaction solvent is DMSO.
In some embodiments, the molar ratio of compound R4-VAD05 to condensing agent is from 1:1.0 to 1:3.0; or the molar ratio is 1:1.2-1:2.0.
In some embodiments, the molar ratio of compound R4-VAD05 to base is from 1:2.0 to 1:6.0; or the molar ratio is 1:2.5-1:5.5; or the molar ratio is 1:3.0-1:5.0.
In some embodiments, the molar ratio of the compound R4-VAD05 to glycine or salt thereof is from 1:1.0 to 1:3.0; or the molar ratio is 1:1.2-1:2.5; or the molar ratio is 1:1.5-1:2.0.
In some embodiments, the reaction temperature of the reaction is from 0 ℃ to 100 ℃; or the reaction temperature is 10-80 ℃; or the reaction temperature is 20-60 ℃; or the reaction temperature is 30-50 ℃.
In some embodiments, the reaction time of the reaction is from 10 minutes to 10 hours; or the reaction time is 20min-8h; or the reaction time is 30min-5h; or the reaction time is 1h-3h.
In some embodiments, the post-processing includes: stopping the reaction, dropwise adding hydrochloric acid under stirring to adjust the pH to about 1-4 for crystallization, and carrying out suction filtration.
In some embodiments, the post-processing includes: washing the filter cake with water, and vacuum drying; or the filter cake is washed by adding 10mL-100mL of water and then vacuum dried for 12h-24h at the temperature of 60 ℃ to 100 ℃.
In some embodiments, a method of preparing a valdostat intermediate compound R4-VAD07 comprises: in a reaction solvent, in the presence of a condensing agent and alkali, reacting the compound R4-VAD05 with glycine or glycine salt at 0-100 ℃, after the reaction, dropwise adding hydrochloric acid to adjust the pH to be 1-4 for crystallization under stirring, filtering, washing a filter cake with water, and then vacuum-drying to constant weight to obtain the compound R4-VAD07.
In some embodiments, a method of preparing a valdostat intermediate compound R4-VAD07 comprises: reacting a compound R4-VAD05 with a condensing agent in a reaction solvent at 0-100 ℃; then reacting glycine or a salt thereof at 0-100 ℃ in the presence of a base; after the reaction is finished, hydrochloric acid is added dropwise under stirring to adjust the pH to be 1-4 for crystallization, suction filtration is carried out, a filter cake is washed by water and then is dried in vacuum until the weight is constant, and the compound R4-VAD07 is prepared.
In some embodiments, a method of preparing a valdostat intermediate compound R4-VAD07 comprises: in DMSO, in the presence of CDI and DIPEA, reacting the compound R4-VAD05 with glycine or a salt thereof at 0-60 ℃, after the reaction, dropwise adding hydrochloric acid to adjust the pH to be 1-3 for crystallization under stirring, filtering, washing a filter cake with water, and drying under vacuum under heating to constant weight to obtain the compound R4-VAD07.
In some embodiments, a method of preparing a valdostat intermediate compound R4-VAD07 comprises: in DMSO, the compound R4-VAD05 is reacted with CDI at 0-60 ℃; then reacting with glycine or its salt in the presence of DIPEA at 0-60 ℃; after the reaction is finished, hydrochloric acid is added dropwise under stirring to adjust the pH to be 1-3 for crystallization, suction filtration is carried out, a filter cake is washed by adding water, and vacuum drying is carried out under heating until the constant weight is achieved, thus obtaining the compound R4-VAD07.
In some embodiments, a method of preparing a valdostat intermediate compound R4-VAD07 comprises: in DMSO, in the presence of CDI and DIPEA, reacting the compound R4-VAD05 with glycine or a salt thereof at 0-60 ℃, after the reaction, dropwise adding hydrochloric acid to adjust the pH to be 1-3 for crystallization under stirring, filtering, washing a filter cake with water, and vacuum drying under heating to constant weight to obtain the compound R4-VAD07; wherein, the mol ratio of the compound R4-VAD05 to the condensing agent is 1:1.0-1:3.0, the mol ratio of the compound R4-VAD05 to the alkali is 1:2.0-1:6.0, and the mol ratio of the compound R4-VAD05 to the glycine or the salt thereof is 1:1.0-1:3.0.
In some embodiments, the preparation method provided by the invention can further comprise the steps of reacting the compound VADB-004 in the presence of alkali, performing post-treatment to obtain R4-VAD05,
The base is an alkali metal hydroxide.
In some embodiments, the base is sodium hydroxide or potassium hydroxide or a combination thereof. The feeding molar ratio of the alkali to the compound VADB-004 is 1:1.0-1:4.0; or the molar ratio is 1:2.0-1:3.0.
In some embodiments, the aqueous base solution has a concentration of 1.0mol/L to 2.0mol/L.
In some embodiments, the post-processing includes: stopping the reaction, cooling to room temperature, regulating the pH value to about 1-4 with concentrated hydrochloric acid, precipitating solid, filtering, washing a filter cake with H 2 O, and vacuum drying; or the post-processing includes: stopping the reaction, cooling to room temperature, regulating pH to about 1-4 with concentrated hydrochloric acid, precipitating solid, suction filtering, washing the filter cake with 100-300 mL H 2 O, and vacuum drying at 60-100deg.C for 12-24 hr.
In some embodiments, compound VADB-004 reacts in the presence of aqueous sodium hydroxide at 40-100 ℃, after the reaction is completed, the reaction is stopped, the temperature is reduced to room temperature, the pH is adjusted to 1-3 by hydrochloric acid, solid is separated out, suction filtration is carried out, and the filter cake is washed by water and then dried in vacuum, thus obtaining R4-VAD05.
In another aspect of the invention, there is provided a compound having the structure shown in R4-VAD 05:
the compound R4-VAD07 can be quickly and conveniently prepared through the R4-VAD05, which is beneficial to improving the yield.
The preparation method of the valdostat intermediate provided by the invention can obtain the intermediate compound R4-VAD07, achieves the aim of the invention, has the advantages of short reaction route, high yield, simple and easily obtained raw materials, lower cost and controllable reaction condition temperature, and is suitable for industrial scale-up production.
In the description of the present invention, it should be understood that the terms "first," "second," and the like are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. In the description of the present invention, the meaning of "a plurality" is two or more, unless explicitly defined otherwise.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
In the present invention, the expressions "compound a" and "compound represented by formula a" and "formula a" mean the same compound.
Detailed Description
In order to better understand the technical solution of the present invention, the following further discloses some non-limiting examples, which are further described in detail.
The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
In the present invention, mmol represents millimoles; min represents minutes; h represents hours; g represents gram; ml represents milliliters; DMF means N, N-dimethylformamide, THF means tetrahydrofuran; CDI represents N, N' -carbonyldiimidazole; EDCI stands for 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide; DCC represents a bicyclic ring hexyl carbodiimide; pyBOP represents benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate; DIPEA represents N, N-diisopropylethylamine; TEA represents triethylamine; DMAP represents 4-dimethylaminopyridine; DABCO represents triethylenediamine; DMSO represents dimethyl sulfoxide; DMAC means N, N-dimethylacetamide.
EXAMPLE 1 preparation of the Compound 5- (3-chlorophenyl) -3-methoxy-2-pyridinecarboxylic acid (R4-VAD 05)
80.0G VADB-004, 47.9g sodium hydroxide and 800mL water are added into a reaction bottle at room temperature, stirring is carried out at a temperature of 100 ℃ for 4 hours, sampling detection HPLC results show that the raw materials are completely reacted, the reaction is stopped, the temperature is reduced to the room temperature, the pH value of concentrated hydrochloric acid is regulated to about 2, solid is separated out, suction filtration is carried out, a filter cake is added with 160mL H 2 O for washing, and then vacuum drying is carried out at 80 ℃ for 12 hours, 82.2g of off-white solid is obtained, the yield is 95.3 percent, the purity is 97 percent, MS is [ M+1] =264.0, nuclear magnetic 1H NMR (400 MHz, DMSO) delta 8.49 (s, 1H), 7.94 (s, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.54 (s, 2H) and 3.97 (s, 3H).
EXAMPLE 2 preparation of the Compound N- (5- (3-chlorophenyl) -3-methoxypyridine-2-carbonyl) glycine (R4-VAD 07)
Adding 25g of R4-VAD05, 30.7g CDI,150ml DMSO into a reaction bottle at room temperature, heating to 45 ℃ completely, stirring and reacting for 1h, then cooling to 30 ℃, adding 21.4g of glycine, 58.2g of DIPEA, adding 30 ℃ completely and reacting for 3h, sampling and detecting HPLC (high performance liquid chromatography) results to show that the raw materials are completely reacted, stopping reacting, dropwise adding concentrated hydrochloric acid under stirring to adjust pH to about 2 for crystallization, filtering, adding 50mL of water into a filter cake, washing at 80 ℃ and vacuum drying for 12h to obtain 27.5g of off-white solid product, wherein the yield is 90.6%, the purity is 98%, MS is [ M+1] = 321.1, and nuclear magnetism is obtained 1H NMR(400MHz,DMSO)δ8.51(s,1H),8.24(s,1H),7.92(s,1H),7.86(s,1H),7.79(d,J＝7.2Hz,1H),7.60–7.47(m,2H),3.97(s,3H),3.59(s,2H).
EXAMPLE 3 preparation of the Compound N- (5- (3-chlorophenyl) -3-hydroxypyridine-2-carbonyl) glycine (Vadadurat)
Adding 20g of R4-VAD07, 50.6g of concentrated hydrochloric acid and 105.0g of acetic acid into a reaction bottle at room temperature, heating to 100 ℃ for reaction, sampling for 24 hours, detecting HPLC (high performance liquid chromatography) results to show that the raw materials are completely reacted, stopping the reaction, cooling the reaction liquid to 0-5 ℃, dropwise adding 50% sodium hydroxide solution to adjust the pH to be 2, preserving the temperature to 0-5 ℃ for crystallization for 3 hours, filtering, recrystallizing a filter cake by using a mixed solvent of ethyl acetate and normal hexane to obtain an off-white solid, and drying at 60 ℃ for 12 hours in vacuum to obtain a finished product Vadadurat 18g, wherein the yield is 94.1% and the purity is 98%. MS: [ M+1] =307.0, nuclear magnetism 1H NMR(400MHz,DMSO)δ12.37(s,1H),9.35(t,J＝5.6Hz,1H),8.82–8.39(m,1H),7.93(d,J＝24.3Hz,1H),7.85–7.68(m,2H),7.65–7.44(m,2H),4.12–3.95(m,2H).
While the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the invention. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.

Claims (4)

1. A process for preparing the compound R4-VAD07,
Step (1): preparation of R4-VAD 05: the compound VADB-004 reacts in the presence of alkali, and R4-VAD05 is obtained after post treatment,
The alkali is alkali metal hydroxide;
Step (2): preparation of R4-VAD07,
The method comprises the steps of reacting a compound R4-VAD05 with glycine or a salt thereof in a reaction solvent in the presence of a condensing agent and alkali, wherein the reaction time of the reaction is 30min-5h; after post-treatment, the compound R4-VAD07 is prepared; wherein the condensing agent is CDI, and the base is DIPEA; ; the reaction solvent is DMSO; the molar ratio of the compound R4-VAD05 to the condensing agent is 1:1.0-1:3.0, the molar ratio of the compound R4-VAD05 to the alkali is 1:2.0-1:6.0, and the molar ratio of the compound R4-VAD05 to the glycine or the salt thereof is 1:1.0-1:3.0; the post-treatment comprises the following steps: stopping the reaction, dropwise adding concentrated hydrochloric acid under stirring to adjust the pH to be 1-4 for crystallization, carrying out suction filtration, adding water into a filter cake, and then carrying out vacuum drying.
2. The process of claim 1, wherein the reaction temperature of the reaction of step (2) is from 20 ℃ to 60 ℃.
3. The method of claim 1, wherein the post-processing of step (1) comprises: stopping the reaction, cooling to room temperature, regulating the pH value to be 1-4 by concentrated hydrochloric acid, precipitating solid, carrying out suction filtration, adding water into a filter cake, and carrying out vacuum drying.
4. A process according to claim 3, wherein the molar ratio of compound VADB-004 to base in step (1) is 1:1.0-1:4.0.
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CN113387882A (en) * 2020-03-11 2021-09-14 东莞市东阳光仿制药研发有限公司 Preparation method of vatacostat and intermediate thereof
GB202011431D0 (en) * 2020-07-23 2020-09-09 Johnson Matthey Plc Polymorphs of vadadustat and methods for preparing the polymorphs

Citations (3)

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Publication number Priority date Publication date Assignee Title
CN1655779A (en) * 2002-03-29 2005-08-17 希龙公司 Substituted benzazoles and methods of their use as inhibitors of Raf kinase
CN105837502A (en) * 2016-04-05 2016-08-10 湖南欧亚生物有限公司 Synthesis method of Vadadustat
CN108473478A (en) * 2015-06-29 2018-08-31 默克专利有限公司 TBK/IKK epsilon inhibitor compounds and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1655779A (en) * 2002-03-29 2005-08-17 希龙公司 Substituted benzazoles and methods of their use as inhibitors of Raf kinase
CN108473478A (en) * 2015-06-29 2018-08-31 默克专利有限公司 TBK/IKK epsilon inhibitor compounds and application thereof
CN105837502A (en) * 2016-04-05 2016-08-10 湖南欧亚生物有限公司 Synthesis method of Vadadustat

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