CN109096148B - Method for preparing vorinostat by using modified mesoporous material through one-pot method - Google Patents
Method for preparing vorinostat by using modified mesoporous material through one-pot method Download PDFInfo
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- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 title claims abstract description 46
- 229960000237 vorinostat Drugs 0.000 title claims abstract description 46
- 238000005580 one pot reaction Methods 0.000 title claims abstract description 10
- 239000013335 mesoporous material Substances 0.000 title description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 68
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 claims abstract description 62
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 28
- 239000011259 mixed solution Substances 0.000 claims abstract description 25
- 238000003756 stirring Methods 0.000 claims abstract description 24
- 239000012046 mixed solvent Substances 0.000 claims abstract description 16
- 239000000243 solution Substances 0.000 claims abstract description 16
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 11
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000008878 coupling Effects 0.000 claims abstract description 5
- 238000010168 coupling process Methods 0.000 claims abstract description 5
- 238000005859 coupling reaction Methods 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 239000000376 reactant Substances 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- 239000007787 solid Substances 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000007822 coupling agent Substances 0.000 claims description 20
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000005406 washing Methods 0.000 claims description 16
- RMIBXGXWMDCYEK-UHFFFAOYSA-N oxonane-2,9-dione Chemical compound O=C1CCCCCCC(=O)O1 RMIBXGXWMDCYEK-UHFFFAOYSA-N 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 11
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- YNBDVONJRSJFLP-UHFFFAOYSA-N 8-(hydroxyamino)-8-oxooctanoic acid Chemical compound ONC(=O)CCCCCCC(O)=O YNBDVONJRSJFLP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 239000006227 byproduct Substances 0.000 claims description 5
- 235000019441 ethanol Nutrition 0.000 claims description 5
- 230000001376 precipitating effect Effects 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical class [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 2
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 2
- 238000002203 pretreatment Methods 0.000 claims description 2
- 239000012265 solid product Substances 0.000 claims description 2
- 238000003828 vacuum filtration Methods 0.000 claims description 2
- 239000006087 Silane Coupling Agent Substances 0.000 claims 1
- 230000035484 reaction time Effects 0.000 abstract description 9
- 239000013067 intermediate product Substances 0.000 abstract description 4
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 238000007781 pre-processing Methods 0.000 abstract 2
- 238000002360 preparation method Methods 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000000746 purification Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 201000005962 mycosis fungoides Diseases 0.000 description 3
- LVCDXCQFSONNDO-UHFFFAOYSA-N n-benzylhydroxylamine Chemical compound ONCC1=CC=CC=C1 LVCDXCQFSONNDO-UHFFFAOYSA-N 0.000 description 3
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- NZRWECQCBREPPG-UHFFFAOYSA-N 8-amino-8-oxooctanoic acid Chemical compound NC(=O)CCCCCCC(O)=O NZRWECQCBREPPG-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000002156 adsorbate Substances 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 150000003441 suberic acid derivatives Chemical class 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- KOVPXZDUVJGGFU-UHFFFAOYSA-N 8-methoxy-8-oxooctanoic acid Chemical compound COC(=O)CCCCCCC(O)=O KOVPXZDUVJGGFU-UHFFFAOYSA-N 0.000 description 1
- HZLLHGVQEZDRGO-UHFFFAOYSA-N 8-methoxy-8-oxooctanoic acid hydrochloride Chemical compound Cl.COC(=O)CCCCCCC(O)=O HZLLHGVQEZDRGO-UHFFFAOYSA-N 0.000 description 1
- 102000003964 Histone deacetylase Human genes 0.000 description 1
- 108090000353 Histone deacetylase Proteins 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- RBVFKMBFVHRPCU-UHFFFAOYSA-N n-trimethylsilylhydroxylamine Chemical compound C[Si](C)(C)NO RBVFKMBFVHRPCU-UHFFFAOYSA-N 0.000 description 1
- PUIBKAHUQOOLSW-UHFFFAOYSA-N octanedioyl dichloride Chemical compound ClC(=O)CCCCCCC(Cl)=O PUIBKAHUQOOLSW-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0272—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255
- B01J31/0274—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255 containing silicon
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a method for preparing vorinostat in a modified mesoporous silica coupling/catalysis system by a one-pot method, which comprises the following steps: preparing hydrophilic modified mesoporous silica as a coupling/catalyst; preprocessing suberic acid by using hydrophilic modified mesoporous silica in a mixed solvent to prepare a preprocessing solution; adding hydroxylamine or a hydrochloride reactant thereof and a reaction promoter into the pretreated mixed solution, and stirring for reaction for 1-2 hours; adjusting the pH value of the mixed solution to 10-12 by alkali, and adding aniline to react for 2-3h to obtain vorinostat. The method of the invention does not need to separate and purify intermediate products, shortens the reaction time, reduces the post-treatment difficulty by using a special catalyst, and improves the yield and the purity of vorinostat.
Description
Technical Field
The invention relates to a synthesis method of a drug compound, in particular to a synthesis method of vorinostat, and belongs to the field of organic synthesis and pharmaceutical chemical synthesis.
Background
Suberoylanilide hydroxamic acid (also known as N-hydroxy-N' -phenyloctanediamide, known under the trade name Vorinostat, is a novel anticancer drug that inhibits protein deacetylase and is marketed in the us 2006, and is suitable for treating a skin cancer called cutaneous cell lymphoma (CTCL). The specific structural formula is as follows:
for the preparation of suberoylanilide hydroxamic acid (hereinafter referred to as vorinostat), various routes are currently disclosed, for example:
patent application WO 2006/127319 discloses a process for the preparation of vorinostat and its polymorphs, comprising amidation of suberic acid and aniline, esterification of the monoamide product with methanol, and the final reaction with hydroxylamine hydrochloride and sodium methoxide. The method has long route, multiple steps, harsh reaction temperature and conditions, and low total yield which is less than 25%. Worse still, the intermediate product is not purified completely, resulting in low purity of the final product, requiring multiple additional purification steps.
The prior art (j.med. chem., 1995, vol.38(8), 1411-. The method adopts high temperature of 190 ℃, improves the treatment cost and the impurity content, and can obtain the product only by carrying out aminolysis reaction on the product and hydroxylamine hydrochloride for 26 hours through ion exchange resin esterification for 22 hours, and the reaction time is long.
An alternative process for the preparation of vorinostat is reported in US5369108, which involves the reaction by introducing hydroxylamine hydrochloride, benzylhydroxylamine and (trimethylsilyl) -hydroxylamine, respectively, in the presence of suberoyl chloride, aniline starting material. Specifically, taking benzylhydroxylamine as an example, the method is as follows: converting the monomethyl suberate to monomethyl suberate-chloride by means of oxalyl chloride, which is converted to suberic acid monoamide by treatment with aniline and potassium hydroxide; benzylhydroxylamine and 1, 3-Dicyclohexylcarbodiimide (DCC) were used to treat suberic acid monoamide and subjected to hydrogenolysis to yield vorinostat, with a yield of up to 65%.
Also prior art (OPPI Briefs, 2001, vol.33(4), 391-. However, in this process, there is competition between the formation of the octanedioic anhydride and the linear anhydride, hindered by the formation of process impurities and by competing reactions, and it is therefore very difficult to isolate pure octanedioic anhydride from the reaction mixture. In addition, conversion of the octanoanilide acid to the mixed anhydride is a highly unstable reversible reaction, resulting in poor reproducibility, low yield, and unsuitability for stable industrial production.
In addition, chinese patent CN102264694B discloses a process for the preparation of vorinostat, which comprises two routes for the preparation of vorinostat, one being the reaction of suberic acid with aniline, or a salt thereof, under the action of a coupling agent to form suberic acid and the reaction of the suberic acid with hydroxylamine, or a salt thereof, to obtain vorinostat; the other way is to obtain suberic acid monoacylhydroxylamine under the action of a coupling agent by firstly reacting suberic acid and hydroxylamine hydrochloride and then reacting with aniline to obtain vorinostat. The method adopts a special coupling agent to realize the improvement of yield to a certain extent, but the reaction time of amidation is still longer, and in addition, the defect of lower product purity is not improved.
In summary, the methods disclosed in the prior art almost all require long reaction time and many reaction steps to obtain the product, and require isolation and purification of reaction intermediates, resulting in low purity and low yield; the prior art does not disclose a suitable catalyst and the reaction efficiency is not high.
Because two carboxyl groups of suberic acid have no selectivity, the prior art adopts some special technical means for achieving the purpose of high-selectivity products. For example, in the presence of a coupling agent (e.g., 1, 3-Dicyclohexylcarbodiimide (DCC), 1' -Carbonyldiimidazole (CDI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1, 3-Diisopropylcarbodiimide (DIC), etc.), which is used to selectively control the carboxyl function in suberic acid, the modified suberic acid may be reacted with aniline or hydroxylamine in any order, although the yield may be improved by improving the reaction selectivity, but the reaction efficiency is not improved and the reaction time is longer.
In summary, the methods disclosed in the prior art have obvious disadvantages in the preparation process: almost all require long reaction times and more reaction steps, as well as isolation and purification of intermediates, resulting in low yields and low purity of the product; is not beneficial to the industrialized production.
Therefore, a direct preparation method of vorinostat without isolation and/or purification of intermediate compounds is highly desired, and it is required to be able to meet the yield requirements of industrial production and the purity requirements of pharmaceutical products.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a suitable modified mesoporous silica catalyst and a method which is simple in steps and low in cost and is used for preparing vorinostat with high yield and high purity.
Through a great deal of research on the catalyst, the invention discovers that the mesoporous silica material modified by the suberic anhydride and the coupling agent is used for replacing the coupling agent modified suberic acid in the prior art, so that the dual effects of the coupling agent and the catalyst can be achieved, and the selective reaction of the suberic acid can be well promoted.
Specifically, the invention provides a method for preparing vorinostat by a one-pot method under a mesoporous silica coupling/catalysis system modified by suberic anhydride and a coupling agent, which comprises the following steps:
(1) preparing mesoporous silica modified by suberic anhydride and coupling agent as a coupling/catalyst;
(2) pre-treating suberic acid with modified mesoporous silica in a mixed organic solvent for 1-3 h to prepare a pre-treatment solution;
(3) adding hydroxylamine or a hydrochloride reactant thereof and a reaction promoter into the pretreated mixed solution, and stirring for reaction for 1-2 hours to generate a reaction mixture containing an intermediate N-hydroxy-7-carboxyl-heptanamide;
(4) without separating and purifying an intermediate, adjusting the pH of the mixed solution to 10-12 by using alkali, adding aniline to react for 2-3h, and carrying out post-treatment to obtain the vorinostat.
Wherein the mixed solvent is a mixed solvent of THF and DMF, and preferably, the volume ratio of THF to DMF is 1: 0.2-0.5.
Wherein the reaction promoter in step (3) is selected from B-halogenated o-phenylenedioxyborane, such as B-chloro-o-phenylenedioxyborane and B-bromo-o-phenylenedioxyborane.
Preferably, the resulting crude vorinostat product is further purified.
Preferably, in the process of the invention, in step (3), hydroxylamine is used in the form of a salt, most preferably the hydrochloride salt.
Preferably, the hydroxylamine or a salt thereof used in step (3) is used in a molar amount of 1 to 3 times, preferably 1:2 to 3, relative to suberic acid.
In the present invention, the amount of the solvent used in the reaction is not particularly limited, and for example, the amount of the mixed solvent used in the step (2) may be 1 to 10 times by volume (mL) of the millimolar amount of suberic acid, and for example, 1 to 10mL of the mixed solvent may be used for 1mmol of suberic acid.
Preferably, 2 to 5ml of a mixed solvent can be used for 1mmol of suberic acid.
In the synthesis process of the present invention, unless otherwise specified, the halogen or halogen in the halo group may be, for example, F, Cl, Br or I, preferably Cl, Br, throughout.
Specifically, in the method of the present invention, the preparation process of the suberic anhydride and coupling agent modified mesoporous silica in step (1) is as follows:
(a) stirring and reacting equimolar suberic anhydride and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) in KH-550 at 0-5 ℃ for 5-10 min, and performing vacuum filtration to dry the solid;
(b) dispersing 10-50 nm mesoporous silica particles in methanol or ethanol at room temperature, and adjusting the pH to 9-10 to prepare mesoporous silica dispersion liquid; dispersing a certain amount of the solid in ethanol, slowly adding the solid into the mesoporous silica dispersion, stirring and reacting for 4-8 h at 25-30 ℃, after the reaction is finished, centrifugally separating, washing the solid with absolute ethanol for 1-2 times, dispersing the solid in a methanol-30-37 wt% hydrochloric acid mixed solution system (the volume ratio of methanol to hydrochloric acid solution is =3-5:1), and refluxing for 3-5 h at 50-60 ℃; and after the reflux is finished, performing centrifugal separation, washing the solid for 1-2 times by using absolute ethyl alcohol, and performing vacuum drying to obtain the maleic anhydride and EDC modified hydrophilic mesoporous silica particles.
In the method, the specific preparation processes of the step (2) to the step (4) by a one-pot method are as follows:
pretreating suberic acid with hydrophilic modified mesoporous silica in a THF/DMF mixed solvent at 25-30 ℃ for 1-3 h to prepare a pretreatment solution, wherein the dosage ratio of the suberic acid to the modified mesoporous silica is 1mmol: 0.5-1g, and the dosage ratio of the suberic acid to the mixed solvent is 1mmol:2-5 ml;
adding hydroxylamine hydrochloride and B-halogenated o-phenylenedioxyborane into the pretreated mixed solution after the pretreatment, and stirring for reacting for 1-2 h to generate a reaction mixture containing an intermediate N-hydroxy-7-carboxyl-heptanamide, wherein the molar ratio of the suberic acid to the hydroxylamine hydrochloride is 1:2-3, and the molar amount of the B-halogenated o-phenylenedioxyborane is 5-10% of that of the suberic acid; adjusting the pH value of the mixed solution to 10-12, adding aniline, and reacting for 2-3h to obtain vorinostat mixed solution;
post-treatment of the reaction solution: filtering to remove solid and by-product, vacuum concentrating the filtrate, adding into dichloromethane, washing the organic solution with water, and drying with anhydrous sodium sulfate; and (3) evaporating the organic solvent at 40 ℃ in vacuum, adding acetonitrile, stirring and dissolving at 50 ℃ for 3-5 minutes, cooling, precipitating, filtering, washing with acetonitrile, and drying the washed solid in vacuum to obtain the vorinostat.
Wherein the volume usage ratio of THF to DMF in the mixed solvent is 1: 0.2-0.5.
Preferably, in the process of the invention, the vorinostat obtained is further purified by the following steps:
adding the crude vorinostat into a mixed solution of saturated ammonia water/acetonitrile (the volume ratio of the ammonia water to the acetonitrile is 1:5-10) at the temperature of 30 ℃, wherein the dosage ratio is 1g:10-15 ml; stirring at 55-60 deg.C, maintaining the temperature, dissolving, cooling to 10-15 deg.C to precipitate, filtering, washing solid with acetonitrile, and vacuum drying to obtain refined product.
The room temperature referred to in the present invention means 25 ℃. + -. 2 ℃ and when washing the product, it is preferred to use a cooling solvent, for example 0 to 15 ℃ or 0 to 10 ℃.
In the present invention, the reaction can be monitored and tracked by methods conventional in the art, such as TLC, LCMS, GCMS, etc., and the end of the reaction means that TLC detects that the excessive raw material has disappeared or that less than 2% of the excessive raw material remains in LCMS, GCMS.
In the present invention, the source of the 10-50 nm mesoporous silica used is not particularly limited, and it may be commercially available mesoporous silica or may be prepared according to a method generally used in the art.
After the mesoporous silica is used, the mesoporous silica can be regenerated and recycled by a method of removing adsorbates and then modifying the mesoporous silica again, so that the cost is further reduced. The method for removing the adsorbate may be performed by referring to a method conventional in the art.
In addition, in other aspects of the invention, there is provided vorinostat as prepared according to the above process according to the invention.
The invention also provides a pharmaceutical composition comprising vorinostat prepared according to the invention. Preferably, the pharmaceutical composition is suitable for the treatment of cancer, preferably skin cancer, more preferably cutaneous T-cell lymphoma (CTCL).
In conclusion, the method for preparing vorinostat by the one-pot method provided by the invention has the advantages that the intermediate product is not required to be separated and purified, the operation steps are simpler, the reaction conditions are mild, the selectivity is good, the catalytic effect is excellent due to the modified mesoporous silica serving as the coupling agent and the catalyst, the reaction time is shortened, and the yield and the purity of vorinostat are improved.
Detailed Description
The present invention is described in detail below with reference to specific examples, but the use and purpose of these exemplary embodiments are merely to exemplify the present invention, and do not set forth any limitation on the actual scope of the present invention in any form, and the scope of the present invention is not limited thereto.
Example 1:
preparation of the mesoporous silica modified by the suberic anhydride/coupling agent:
(1) adding 0.5 mol of octandianhydride and 0.5 mol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride into 100ml of coupling agent KH-550, stirring and reacting for 5 min under the ice bath condition, cooling to room temperature, filtering, and drying in vacuum to obtain a solid A;
(2) weighing 50 g of 30 nm mesoporous silica particles, dispersing in 300ml of 95% methanol, adjusting the pH to 9.5 with ammonia water, and uniformly stirring to obtain a mesoporous silica dispersion liquid;
(3) dispersing 2.5 g of the solid A in 30 ml of ethanol, slowly adding the solid A into the mesoporous silica dispersion, keeping the temperature at 30 ℃ and slowly stirring for reaction for 6 hours, centrifugally separating after the reaction is finished, dispersing the solid in a 120ml methanol-hydrochloric acid mixed solution system (methanol: 30wt% hydrochloric acid volume ratio =5:1) after the solid is washed by absolute ethyl alcohol, and refluxing for 5 hours at 50 ℃; and after the reflux is finished, performing centrifugal separation, washing the solid for 2 times by using absolute ethyl alcohol, and performing vacuum drying to obtain the suberic anhydride/coupling agent EDC modified mesoporous silica particles with the particle size range of 120-150 nm.
Example 2
The one-pot method for preparing vorinostat:
adding 25g of the prepared suberic anhydride/coupling agent EDC modified mesoporous silica and 0.1mol of suberic acid into a mixed solvent consisting of 300ml of THF and 100ml of DMF at 25 ℃, keeping the temperature, and slowly stirring for reaction for 1 h to prepare a pretreatment solution;
adding 0.2 mol of hydroxylamine and 5 mmol of B-chloro-o-phenylenedioxyborane into the pretreated mixed solution after the pretreatment, and stirring and reacting for 2 hours at the temperature of 30 ℃ to generate a reaction mixture containing an intermediate N-hydroxy-7-carboxyl-heptanamide;
adjusting the pH value of the reaction mixed solution to 11 by using 1mol/l of sodium hydroxide, adding aniline, stirring and reacting for 3 hours to obtain a mixed solution containing the vorinostat product;
and (3) post-treatment process of the reaction liquid: filtering the reacted mixed solution to remove the catalyst and solid by-products, concentrating the filtrate to 40 ml in vacuum, adding the filtrate into 200 ml dichloromethane, washing the organic solution with water, and drying the organic solution with anhydrous sodium sulfate; and (3) evaporating the organic solvent at 40 ℃ in vacuum, adding acetonitrile, stirring and dissolving for 5 minutes at 50 ℃, cooling, precipitating, filtering, washing with acetonitrile twice, and drying the washed solid in vacuum to obtain the vorinostat. The molar yield based on suberic acid was 80.2%; HPLC purity 99.8%.
13C-NMR(DMSO-d6)：25.04(2C，2x-CH2-)，28.43(2C，2x-CH2-)，32.24(1C，-CH2-)，36.34(1C，-CH2-)，119.01(2C，Ar-C)，122.96(1C，Ar-C)，128.68(2C，Ar-C)，139.24(1C，Ar-C，＝CNH-)，169.23(1C，-CO-)，171.50(1C，-CO-)。
Example 3
The one-pot method for preparing vorinostat:
adding 100g of the prepared suberic anhydride/coupling agent EDC modified mesoporous silica and 0.1mol of suberic acid into a mixed solvent consisting of 400ml of THF and 100ml of DMF at the temperature of 30 ℃, keeping the temperature, and slowly stirring for reaction for 1 h to prepare a pretreatment solution;
adding 0.3 mol of hydroxylamine hydrochloride and 10 mmol of B-bromo-o-phenylenedioxyborane into the pretreated mixed solution after the pretreatment, and stirring at 30 ℃ for reacting for 2 hours to generate a reaction mixture containing an intermediate N-hydroxy-7-carboxyl-heptanamide; adjusting the pH value of the reaction mixed solution to 10 by using potassium hydroxide, adding aniline, stirring and reacting for 3 hours to obtain a mixed solution containing the product vorinostat;
filtering the reacted mixed solution to remove the catalyst and solid by-products, concentrating the filtrate to 50 ml in vacuum, adding the filtrate into 200 ml dichloromethane, washing the organic solution with water, and drying the organic solution with anhydrous sodium sulfate; and (3) evaporating the organic solvent at 40 ℃ in vacuum, adding acetonitrile, stirring and dissolving for 5 minutes at 50 ℃, cooling, precipitating, filtering, washing with acetonitrile twice, and drying the washed solid in vacuum to obtain the vorinostat. The molar yield based on suberic acid was 83.5%; HPLC purity 99.7%.
Comparative example 1
The coupling agent replaces the modified mesoporous silica catalyst:
a mixture of CDI (0.5eq) and DCC (0.8eq) in THF (15vol) was stirred at 25-30 deg.C for 1 hour. Suberic acid (1eq) and hydroxylamine (1eq) in THF (1vol) were added and the mixture was stirred for an additional 1 hour. Then CDI (0.5eq), DCC (0.8eq) and aniline (1eq) were added to the mixture and the mixture was stirred for a further 16-20 hours. The solid by-product was removed by filtration and the filtrate was concentrated in vacuo at 50 ℃ to obtain crude vorinostat. Molar yield = 55-60%; purity by HPLC 95.8%.
Comparative example 2
The same preparation and reaction parameters as in example 2 were used, except that no reaction promoter was added, the yield of vorinostat after the same reaction time was 75.6% with a purity of 99.1%.
Comparative example 3
The same preparation method and reaction parameters as in example 2 were used, except that no reaction accelerator and modified mesoporous silica were added, and the yield of vorinostat after the reaction was 23.6% with a purity of 87.2%.
In conclusion, the invention provides a one-pot synthesis method of vorinostat, in the method, separation and purification of intermediate products are avoided, reaction time is shortened, post-treatment process is simplified and good technical effects are obtained through proper selection/combination of reaction sequence, specific catalyst and accelerant.
It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should also be understood that various alterations, modifications and/or variations can be made to the present invention by those skilled in the art after reading the technical content of the present invention, and all such equivalents fall within the protective scope defined by the claims of the present application.
Claims (5)
1. A method for preparing vorinostat by a one-pot method in the presence of suberic anhydride/coupling agent modified mesoporous silica is characterized by comprising the following steps:
(1) preparing mesoporous silica modified by suberic anhydride and coupling agent as a coupling/catalyst;
(2) pre-treating suberic acid with modified mesoporous silica in a mixed organic solvent for 1-3 h to prepare a pre-treatment solution; wherein the mixed solvent is a mixed solvent of THF and DMF;
(3) adding hydroxylamine or a hydrochloride reactant thereof and a reaction promoter into the pretreated mixed solution, and stirring for reaction for 1-2 hours to generate a reaction mixture containing an intermediate N-hydroxy-7-carboxyl-heptanamide; wherein the accelerator is selected from B-halophthaloxyborane;
(4) without separating and purifying an intermediate, adjusting the pH of the mixed solution to 10-12 by using alkali, adding aniline to react for 2-3h, and performing post-treatment to obtain vorinostat;
wherein, the process for preparing the mesoporous silica modified by the suberic anhydride and the coupling agent in the step (1) is as follows:
(a) stirring and reacting equimolar suberic anhydride and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) in silane coupling agent KH-550 at 0-5 ℃ for 5-10 min, and performing vacuum filtration to dry the solid;
(b) dispersing 10-50 nm mesoporous silica particles in methanol or ethanol at room temperature, and adjusting the pH to 9-10 to prepare mesoporous silica dispersion liquid; dispersing a certain amount of the solid obtained in the step (a) in ethanol, slowly adding the solid into the mesoporous silica dispersion liquid, stirring and reacting for 4-8 h at 25-30 ℃, after the reaction is finished, centrifugally separating, washing the solid with absolute ethanol for 1-2 times, dispersing the solid in a mixed solution system consisting of methanol and 30-37wt% hydrochloric acid, and refluxing for 3-5 h at 50-60 ℃; and after the reflux is finished, performing centrifugal separation, washing the solid for 1-2 times by using absolute ethyl alcohol, and performing vacuum drying to obtain the maleic anhydride and EDC modified hydrophilic mesoporous silica particles.
2. The method of claim 1, wherein: hydroxylamine is used in step (3) as the hydrochloride salt.
3. The method of claim 1, wherein: the specific processes of the step (2) to the step (4) are as follows:
pretreating suberic acid with hydrophilic modified mesoporous silica in a THF/DMF mixed solvent at 25-30 deg.C for 1-3 h to prepare a pretreatment solution, wherein the dosage ratio of suberic acid to modified mesoporous silica is 1mmol: 0.5-1g, and the dosage ratio of suberic acid to mixed solvent is 1mmol:2-5 ml;
adding hydroxylamine hydrochloride and B-halogenated o-phenylenedioxyborane into the pretreated mixed solution after the pretreatment, and stirring for reacting for 1-2 h to generate a reaction mixture containing an intermediate N-hydroxy-7-carboxyl-heptanamide, wherein the molar ratio of the suberic acid to the hydroxylamine hydrochloride is 1:2-3, and the molar amount of the B-halogenated o-phenylenedioxyborane is 5-10% of that of the suberic acid; adjusting the pH value of the mixed solution to 10-12, adding aniline, and reacting for 2-3h to obtain vorinostat mixed solution;
post-treatment of the reaction solution: filtering to remove solid and by-product, vacuum concentrating the filtrate, adding into dichloromethane, washing the organic solution with water, and drying with anhydrous sodium sulfate; and (3) evaporating the organic solvent at 40 ℃ in vacuum, adding acetonitrile, stirring and dissolving at 50 ℃ for 3-5 minutes, cooling, precipitating, filtering, washing with acetonitrile, and drying the washed solid in vacuum to obtain the vorinostat.
4. The production method according to claim 3, characterized in that: the volume usage ratio of THF to DMF in the mixed solvent is 1: 0.2-0.5.
5. The production method according to any one of claims 1 to 4, characterized in that: further purifying the obtained crude vorinostat product by the following steps: adding the crude vorinostat into a saturated ammonia water/acetonitrile mixed solution at the temperature of 30 ℃, stirring and preserving heat at the temperature of 55-60 ℃ for fully dissolving, then cooling to the temperature of 10-15 ℃ for precipitating, filtering, washing solid with acetonitrile, and drying in vacuum to obtain a refined product.
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| CN101939289A (en) * | 2008-02-07 | 2011-01-05 | 基因里克斯(英国)有限公司 | Novel process for the preparation of vorinostat |
| CN106187818A (en) * | 2016-06-27 | 2016-12-07 | 青岛云天生物技术有限公司 | A kind of method preparing cancer therapy drug Vorinostat |
| CN108514641A (en) * | 2018-04-10 | 2018-09-11 | 张海英 | Docetaxel conjugate preparation method based on mesoporous material self-assembly system |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101939289A (en) * | 2008-02-07 | 2011-01-05 | 基因里克斯(英国)有限公司 | Novel process for the preparation of vorinostat |
| CN106187818A (en) * | 2016-06-27 | 2016-12-07 | 青岛云天生物技术有限公司 | A kind of method preparing cancer therapy drug Vorinostat |
| CN108514641A (en) * | 2018-04-10 | 2018-09-11 | 张海英 | Docetaxel conjugate preparation method based on mesoporous material self-assembly system |
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| Direct Amide Synthesis from Equimolar Amounts of Carboxylic Acid and Amine Catalyzed by Mesoporous Silica SBA-15;Mizuki Tamura et al.;《Synthesis》;20151015;第47卷;第769-776页 * |
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