CN113387882A - Preparation method of vatacostat and intermediate thereof - Google Patents
Preparation method of vatacostat and intermediate thereof Download PDFInfo
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- CN113387882A CN113387882A CN202010164678.9A CN202010164678A CN113387882A CN 113387882 A CN113387882 A CN 113387882A CN 202010164678 A CN202010164678 A CN 202010164678A CN 113387882 A CN113387882 A CN 113387882A
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- 238000002360 preparation method Methods 0.000 title abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- 238000000034 method Methods 0.000 claims abstract description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 27
- 239000012065 filter cake Substances 0.000 claims description 23
- 238000000967 suction filtration Methods 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- 238000002425 crystallisation Methods 0.000 claims description 17
- 230000008025 crystallization Effects 0.000 claims description 17
- 238000001816 cooling Methods 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 13
- 239000007810 chemical reaction solvent Substances 0.000 claims description 12
- 238000001291 vacuum drying Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 8
- 238000012805 post-processing Methods 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- 239000002841 Lewis acid Substances 0.000 claims description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 4
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 16
- JGRXMPYUTJLTKT-UHFFFAOYSA-N 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid Chemical compound C1=C(O)C(C(=O)NCC(=O)O)=NC=C1C1=CC=CC(Cl)=C1 JGRXMPYUTJLTKT-UHFFFAOYSA-N 0.000 abstract description 10
- 229950004420 vadadustat Drugs 0.000 abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000013341 scale-up Methods 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 3
- 238000006482 condensation reaction Methods 0.000 abstract description 2
- DYUOYBIHGUNMQN-UHFFFAOYSA-N 3-chloro-5-(3-chlorophenyl)pyridine-2-carbonitrile Chemical compound ClC1=CC=CC(C=2C=C(Cl)C(C#N)=NC=2)=C1 DYUOYBIHGUNMQN-UHFFFAOYSA-N 0.000 abstract 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000004321 preservation Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 230000005311 nuclear magnetism Effects 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 230000008878 coupling Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 3
- ATUOLSDAAPMVJJ-UHFFFAOYSA-N 3,5-dichloropyridine-2-carbonitrile Chemical compound ClC1=CN=C(C#N)C(Cl)=C1 ATUOLSDAAPMVJJ-UHFFFAOYSA-N 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- -1 benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate Chemical compound 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- 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
-
- 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
- C07D213/803—Processes of preparation
Landscapes
- 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 valdoxetamol and an intermediate thereof, belonging to the field of pharmaceutical chemistry. The preparation method comprises the steps of taking 3-chloro-5- (3-chlorphenyl) -2-cyanopyridine as a starting material, carrying out hydrolysis reaction, and carrying out condensation reaction to obtain a compound intermediate; the intermediate compound can be further reacted to obtain vadadustat (kovatat); the method has the advantages of short route, simple and easily-obtained raw materials, low cost and mild reaction conditions, and is suitable for industrial scale-up production.
Description
Technical Field
The invention relates to the field of medicinal chemistry, and in particular relates to a preparation method of valdoxetamol and an intermediate thereof.
Background
Varkovista (Vadadustat), CAS: 1000025-07-9, having the chemical name N- (5- (3-chlorophenyl) -3-hydroxypyridine-2-carbonyl) glycine, 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 structural formula is as follows:
synthetic route of Vadadustat disclosed in US patent 20070299086: 3, 5-dichloro-2-cyanopyridine is used as a starting material, and Vadadustat is obtained through benzyl substitution reaction, hydrolysis, coupling, hydrogenation, substitution, coupling and hydrolysis reaction in 7 steps, wherein the total yield is 9%. The route is long and the yield is low. Wherein, the benzyl substitution reaction in the first step has harsh conditions and cannot be amplified (microwave reaction, 190 ℃), and in addition, the hydrogenation reaction and the coupling reaction are also carried out, 5 times of column chromatography purification are needed totally, the operation is inconvenient, the cost is high, and the route is not suitable for industrial amplification.
A synthetic route for the preparation of Vadadustat is disclosed in US patent US 20120309977: 3-chlorobenzoic acid and 3, 5-dichloro-2-cyanopyridine are used as initial raw materials, and Vadadustat is obtained through catalytic coupling, methoxy substitution, cyano hydrolysis, condensation and ester hydrolysis reaction, and the reaction is carried out for 5 steps.
Therefore, research on a preparation method of Vadadustat and an intermediate thereof is still needed to obtain a preparation method which is simple and convenient to operate, easy to implement, high in yield, high in purity, low in cost, environment-friendly and suitable for industrial scale-up production.
Disclosure of Invention
The invention provides a preparation method of valdoxetamol and an intermediate thereof, wherein the structure of an intermediate compound (6) is as follows:
according to the preparation method, the compound (3) is used as a starting material, a hydrolysis reaction is carried out to obtain the compound (4), the compound (4) and the compound (5) are subjected to a condensation reaction to obtain the compound (6), and the compound (6) can be further subjected to a hydrolysis reaction to obtain vadadustat.
The specific reaction route is as follows:
in one aspect, the invention provides a preparation method of a vatacostat intermediate compound (6),
which comprises reacting a compound (4) with a glycine methyl ester represented by a compound (5) or a salt thereof in a reaction solvent in the presence of a condensing agent, followed by post-treatment to obtain a compound (6). The method for preparing the intermediate compound (6) has the advantages of mild reaction conditions, high yield, simple post-treatment and suitability for industrial amplification.
In some embodiments, the condensing agent is selected from at least one of CDI, EDCI, DCC, or PyBOP. In some embodiments, the condensing agent is CDI, facilitating the production and availability of the target product.
In some embodiments, the reaction solvent is an organic solvent, and may be selected from at least one of DCM, DMSO, DMF, DMAC, or THF. In some embodiments, the reaction solvent is DCM, which facilitates the reaction and work-up.
In some embodiments, the compound (4) to condensing agent molar ratio is 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 (4) to glycine methyl ester represented by compound (5) or a salt thereof is 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 15-70 ℃; or the reaction temperature is 20-60 ℃.
In some embodiments, the reaction time of the reaction is from 10min to 10 h; or the reaction time is 20min-8 h; or the reaction time is 30min-5 h; or the reaction time is 1h-3 h.
In some embodiments, the post-processing comprises: stopping reaction, removing solvent, adding water for crystallization, filtering, washing filter cake with water, and vacuum drying.
In some embodiments, the post-processing comprises: washing the filter cake with water, and vacuum drying; or adding 50mL-200mL of water into the filter cake, washing, and then drying in vacuum at 60-100 ℃ for 12-24 h.
In some embodiments, a method of preparing the intermediate compound (6) of valdoxat comprises: in a reaction solvent, in the presence of a condensing agent, reacting a compound (4) with glycine methyl ester or a salt thereof shown as a compound (5) at 0-100 ℃, removing the solvent after the reaction is finished, adding water for crystallization, performing suction filtration, washing a filter cake with water, and performing vacuum drying to obtain a compound (6).
In some embodiments, a method of preparing the intermediate compound (6) of valdoxat comprises: in a reaction solvent, reacting a compound (4) with glycine methyl ester or a salt thereof represented by a compound (5) at 0 ℃ to 100 ℃ in the presence of a condensing agent; after the reaction is finished, removing the solvent, adding water to separate out crystals, performing suction filtration, washing a filter cake with water, and performing vacuum drying to obtain the compound (6).
In some embodiments, a method of preparing the intermediate compound (6) of valdoxat comprises: in DCM, in the presence of CDI, glycine or a salt thereof shown as a compound (4) and a compound (5) reacts at 0-60 ℃, after the reaction is finished, a solvent is removed, water is added for crystallization, the crystal is filtered, a filter cake is washed by water, and then the filter cake is dried in vacuum to obtain a compound (6).
In some embodiments, a method of preparing the intermediate compound (6) of valdoxat comprises: in DCM, compound (4) is first reacted with CDI at 0 deg.C-60 deg.C; then reacting with glycine methyl ester or salt thereof shown in a compound (5) at 0-60 ℃; after the reaction is finished, removing the solvent, adding water to separate out crystals, performing suction filtration, washing a filter cake with water, and performing vacuum drying to obtain the compound (6).
In some embodiments, a method of preparing the intermediate compound (6) of valdoxat comprises: in DCM, in the presence of CDI, glycine methyl ester or a salt thereof shown as a compound (4) and a compound (5) reacts at 0-60 ℃, after the reaction is finished, a solvent is removed, water is added for crystallization, the filtration is carried out, a filter cake is washed by water, and the vacuum drying is carried out to obtain a compound (6); wherein the molar ratio of the compound (4) to the CDI is 1:1.0-1:3.0, and the molar ratio of glycine or a salt thereof represented by the compound (4) and the compound (5) is 1:1.0-1: 3.0.
In some embodiments, the preparation method of the compound (6) can further comprise reacting the compound (3) in the presence of a base, and performing post-treatment to obtain the compound (4),
the alkali is at least one of sodium methoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide.
In some embodiments, the base is sodium methoxide, sodium hydroxide, potassium hydroxide, or sodium ethoxide, or a combination thereof. The feeding molar ratio of the alkali to the compound (3) is 1:1.0-1: 4.0; or the molar ratio is 1:2.0-1: 3.0.
In some embodiments, the base may be an aqueous base solution; the concentration of the alkali aqueous solution is 1.0mol/L-2.0 mol/L.
In some embodiments, the post-processing comprises: stopping the reaction, cooling to room temperature, removing the solvent, adding a hydrochloric acid aqueous solution, cooling to below 10 ℃, separating out a solid, performing suction filtration, washing a filter cake with water, and performing vacuum drying to obtain a compound (4); or the post-processing comprises: stopping reaction, cooling to room temperature, removing the solvent, adding a hydrochloric acid solution, cooling to below 10 ℃, separating out a solid, performing suction filtration, washing a filter cake with water, and performing vacuum drying at 60-100 ℃ for 12-24 hours; compound (4) is obtained.
In some embodiments, the compound (3) is reacted in a methanol solution of sodium methoxide at 40-100 ℃, then an aqueous solution of sodium hydroxide is added for continuous reaction, after the reaction is finished, the reaction is stopped, the temperature is reduced to room temperature, the solvent is removed, an aqueous solution of hydrochloric acid is added, the temperature is reduced to below 10 ℃, a solid is separated out, the filtration is carried out, a filter cake is washed by water, and the vacuum drying is carried out to obtain the compound (4).
In one aspect, a method of making compound (7) comprises: the compound (6) is reacted in a reaction solvent in the presence of a Lewis acid, and the compound (7) is obtained after the post-treatment,
the Lewis acid is at least one of aluminum trichloride, lithium chloride or magnesium chloride.
The compound (6) can be obtained according to the aforementioned method.
In some embodiments, the lewis acid is aluminum trichloride, lithium chloride, or magnesium chloride, or a combination thereof. The feeding molar ratio of the Lewis acid to the compound (6) is 1:1.0-1: 4.0; or the molar ratio is 1:2.0-1: 3.0.
In some embodiments, the reaction solvent is selected from at least one of DMF, DMAC, DMSO, or NMP; in some embodiments, the reaction solvent is DMF, which facilitates the reaction.
In some embodiments, the post-processing comprises: stopping reaction, cooling to room temperature, adding dilute hydrochloric acid, precipitating solid, performing suction filtration, adding water, acetone, sodium hydroxide and active carbon into a filter cake, continuing to react at 40-80 ℃, performing suction filtration, adding concentrated hydrochloric acid into filtrate for crystallization, cooling to room temperature, performing suction filtration, and performing vacuum drying to obtain the compound (7).
In some embodiments, compound (6) is added with aluminum trichloride in DMF to react at 60-120 ℃, and after the reaction is finished, the reaction is stopped, and after post-treatment, compound (7) is obtained; the post-treatment is to stop the reaction, cool to room temperature, add dilute hydrochloric acid, separate out solid, pump filter, add water, acetone, sodium hydroxide and active carbon to the filter cake, continue to react at 40-80 ℃, pump filter, add concentrated hydrochloric acid to the filtrate for crystallization, cool to room temperature, pump filter, vacuum dry to obtain the compound (7).
In another aspect of the present invention, there is provided a compound having the structure represented by compound (4):
the compound (6) can be prepared quickly and conveniently through the compound (4), which is beneficial to simplifying the reaction process, improving the yield, reducing the cost and facilitating the industrialized production.
The preparation method of the vatacostat intermediate provided by the invention can obtain the intermediate compound (6), the compound (6) is further hydrolyzed to obtain the vatacostat, the purpose of the invention is achieved, the reaction route is short, the yield is high, the raw materials are simple and easy to obtain, the cost is lower, the reaction condition temperature is controllable, and the preparation method is suitable for industrial scale-up production.
In the description of the present invention, it is to 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 relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean 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 invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer 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, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
In the present invention, the expression "compound A" and "compound represented by formula A" and "formula A" means the same compound.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol; min represents minutes; h represents an hour; g represents g; ml means ml; DMF for N, N-dimethylformamide, THF for tetrahydrofuran; CDI represents N, N' -carbonyldiimidazole; EDCI represents 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide; DCC denotes dicyclohexylcarbodiimide; DCM represents dichloromethane; PyBOP represents benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate; DIPEA represents N, N-diisopropylethylamine; TEA represents triethylamine; DMAP represents 4-dimethylaminopyridine; DABCO represents triethylenediamine; DMSO represents dimethyl sulfoxide; DMAC represents N, N-dimethylacetamide; NMP stands for N-methylpyrrolidone.
EXAMPLE 1 preparation of Compound (4)
Adding 0.15kg of compound (3), 1.5L of anhydrous methanol and 0.22kg of sodium methoxide methanol solution (27.5% -31.0%) into a reaction bottle at room temperature, completely heating and carrying out reflux reaction, adding 1.5L of water and 0.06kg of sodium hydroxide after HPLC (high performance liquid chromatography) results show that raw materials are completely reacted, continuously carrying out reflux reaction after the HPLC results show that the raw materials are completely reacted, stopping reaction, concentrating to be dry, adding 0.21kg of concentrated hydrochloric acid for crystallization, cooling to 10 ℃, carrying out suction filtration, and drying a filter cake at 80 ℃ for 14.0h to obtain 128.5g of solid, wherein the yield is 80.9%, and the purity is 97.2%.
MS:[M+1]264.0 nuclear magnetic resonance1H NMR(400MHz,DMSO)δ8.49(s,1H),7.94(s,1H),7.86(s,1H),7.80(s,1H),7.54(s,2H),3.97(s,3H).
EXAMPLE 2 preparation of Compound (4)
Adding 0.25kg of compound (3), 2.5L of anhydrous methanol and 0.36kg of sodium methoxide methanol solution (27.5% -31.0%) into a reaction bottle at room temperature, completely heating and carrying out reflux reaction, adding 2.5L of water and 0.10kg of sodium hydroxide after HPLC (high performance liquid chromatography) results show that raw materials completely react, continuously carrying out reflux reaction after the HPLC results show that the raw materials completely react, stopping reaction, concentrating to be dry, adding 0.35kg of concentrated hydrochloric acid for crystallization, cooling to 10 ℃, carrying out suction filtration, and drying a filter cake at 80 ℃ for 14.0h to obtain 219.5g of solid, wherein the yield is 82.9%, and the purity is 98.1%.
MS:[M+1]264.0 nuclear magnetic resonance1H NMR(400MHz,DMSO)δ8.49(s,1H),7.94(s,1H),7.86(s,1H),7.80(s,1H),7.54(s,2H),3.97(s,3H).
EXAMPLE 3 preparation of Compound (6)
Adding 100.0g of the compound (4), 122.99g of CDI and 500.0ml of DCM into a reaction bottle at room temperature, stirring for reaction at 30 ℃ until the HP LC result shows that the raw materials completely react, adding 66.66g of glycine methyl ester shown as the compound (5) into the reaction bottle, continuing stirring for reaction at 30 ℃ until the HPLC result shows that the raw materials completely react, concentrating until the raw materials are dried, adding 0.95L of water for crystallization, performing suction filtration at room temperature, and drying a filter cake at 80 ℃ for 12 hours to obtain 124.2g of solid, wherein the yield is 97.8% and the purity is 97.3%.
MS:[M+1]Nuclear magnetism of 335.11H NMR(400MHz,DMSO)δ8.79(t,J＝5.9Hz,1H),8.52(s,1H),7.96(s,1H),7.86(s,1H),7.82(d,J＝7.0Hz,1H),7.61–7.51(m,2H),4.03(d,J＝6.0Hz,2H),3.96(s,3H),3.67(s,3H).
EXAMPLE 4 preparation of Compound (6)
Adding 0.25kg of the compound (4), 0.31kg of CDI and 1.25L of DCM into a reaction bottle at room temperature, stirring for reaction at 30 ℃ until HPLC results show that the raw materials completely react, adding 0.17kg of glycine methyl ester shown as the compound (5) into the reaction bottle, continuing stirring for reaction at 30 ℃ until HPLC results show that the raw materials completely react, concentrating until the raw materials are dried, adding 2.5L of water for crystallization, performing suction filtration at room temperature, and drying a filter cake at 80 ℃ for 12 hours to obtain 311.4g of solid, wherein the yield is 98.1% and the purity is 97.2%.
MS:[M+1]Nuclear magnetism of 335.11H NMR(400MHz,DMSO)δ8.79(t,J＝5.9Hz,1H),8.52(s,1H),7.96(s,1H),7.86(s,1H),7.82(d,J＝7.0Hz,1H),7.61–7.51(m,2H),4.03(d,J＝6.0Hz,2H),3.96(s,3H),3.67(s,3H).
EXAMPLE 5 preparation of Compound (7)
20.0g of Compound (6), 80.0ml of DMF, 9.56g of AlCl were added to a reaction flask at room temperature3Heating to 85 ℃, carrying out heat preservation reaction until HPLC results show that the raw materials completely react, stopping the reaction, cooling the reaction liquid to 30 ℃, dropwise adding 200ml of dilute hydrochloric acid for crystallization, carrying out suction filtration at room temperature, adding the filter cake into another reaction bottle, then adding 200.0ml of water, 60.0ml of acetone, 4.78g of sodium hydroxide and 2.0g of activated carbon, heating to 60 ℃ after the completion of the addition, carrying out heat preservation reaction for 1.0h, carrying out suction filtration on the reaction liquid to obtain a filtrate, dropwise adding 18.15g of concentrated hydrochloric acid into the filtrate for crystallization, cooling to room temperature, carrying out suction filtration to obtain a white-like solid, and drying at 80 ℃ for 16h to obtain 15.50g of the finished compound (7), wherein the yield is 84.70% and the purity is 99.9%.
MS:[M+1]307.0 nuclear magnetism1H 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).
EXAMPLE 6 preparation of Compound (7)
100.0g of Compound (6), 400.0ml of DMF, 47.80g of AlCl were added to a reaction flask at room temperature3Heating to 85 ℃, carrying out heat preservation reaction until HPLC results show that the raw materials completely react, stopping the reaction, cooling the reaction liquid to 30 ℃, dropwise adding 1.0L of dilute hydrochloric acid for crystallization, carrying out suction filtration at room temperature, adding a filter cake into another reaction bottle, then adding 1.0L of water, 0.3L of acetone, 23.90g of sodium hydroxide and 10.0g of activated carbon, heating to 60 ℃, carrying out heat preservation reaction for 1.0h, carrying out suction filtration on the reaction liquid to obtain a filtrate, dropwise adding 90.76g of concentrated hydrochloric acid into the filtrate for crystallization, cooling to room temperature, carrying out suction filtration to obtain a white-like solid, and drying at 80 ℃ for 16h to obtain 78.1g of a finished product compound (7), wherein the yield is 85.2% and the purity is 99.9%.
MS:[M+1]307.0 nuclear magnetism1H 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).
EXAMPLE 7 preparation of Compound (7)
Adding 5.0g of compound (6), 50.0ml of DMAC, 3.80g of LiCl and 15.43g of p-toluenesulfonic acid into a reaction bottle at room temperature, heating to 100 ℃, carrying out heat preservation reaction, stopping the reaction after HPLC (high performance liquid chromatography) results show that raw materials completely react, cooling reaction liquid to 30 ℃, dropwise adding 50ml of dilute hydrochloric acid for crystallization, carrying out suction filtration at room temperature, adding filter cakes into another reaction bottle, adding 50.0ml of water, 15.0ml of acetone, 1.19g of sodium hydroxide and 0.5g of activated carbon, heating to 60 ℃, carrying out heat preservation reaction for 1.0h, carrying out suction filtration to obtain filtrate, dropwise adding 4.54g of concentrated hydrochloric acid for crystallization, cooling to room temperature for suction filtration to obtain white-like solid, drying at 80 ℃ for 16h to obtain 3.5g of finished compound (7), wherein the yield is 76.4% and the purity is 99.1%.
MS:[M+1]307.0 nuclear magnetism1H 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 the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. A process for producing the compound (6),
which comprises reacting a compound (4) with glycine methyl ester represented by a compound (5) or a salt thereof in a reaction solvent in the presence of a condensing agent, followed by post-treatment to obtain a compound (6); wherein the condensing agent is selected from at least one of CDI, EDCI, DCC and PyBOP.
2. The method according to claim 1, wherein the molar ratio of the compound (4) to the condensing agent is 1:1.0 to 1:3.0, or the molar ratio of the compound (4) to the glycine methyl ester represented by the compound (5) or the salt thereof is 1:1.0 to 1: 3.0.
3. The process of claim 1, the reaction solvent is selected from at least one of DCM, DMF, DMAC, DMSO, and THF; and/or the reaction temperature of the reaction is from 20 ℃ to 60 ℃.
4. The method of claims 1-5, the post-processing comprising: stopping reaction, removing solvent, adding water for crystallization, filtering, washing filter cake with water, and vacuum drying.
5. The method of claim 1, further comprising reacting the compound (3) in the presence of a base, and performing a post-treatment to obtain a compound (4),
the alkali is at least one of sodium methoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide.
6. The method of claim 5, the post-processing comprising: stopping reaction, cooling to room temperature, removing the solvent, adding a hydrochloric acid solution, cooling to below 10 ℃, separating out a solid, carrying out suction filtration, adding water to wash a filter cake, and carrying out vacuum drying to obtain the compound (4).
7. The process according to claim 5, wherein the molar ratio of the compound (3) to the base is from 1:1.0 to 1: 4.0.
8. A method of preparing compound (7), comprising: the compound (6) prepared by the method according to claim 1 is reacted in a reaction solvent in the presence of a Lewis acid, and the compound (7) is obtained after the post-treatment,
the Lewis acid is at least one of aluminum trichloride, lithium chloride or magnesium chloride.
9. The method of claim 8, wherein the reaction solvent is at least one selected from the group consisting of DMF, DMAC, DMSO and NMP.
10. A compound having the structure shown in Compound (4):
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