CN115974856A - Preparation method of medicine of vatistal for treating adult T cell leukemia lymphoma - Google Patents
Preparation method of medicine of vatistal for treating adult T cell leukemia lymphoma Download PDFInfo
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Abstract
The invention relates to a preparation method of valacitrex, in particular to a preparation method of an intermediate (2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-formamide, and the intermediate is used for preparing the valacitrex.
Description
Technical Field
The invention belongs to the field of chemical drugs, and particularly relates to a novel preparation method of a relapsed or refractory adult T cell leukemia-lymphoma treatment drug Valemetostat (Valemetostat).
Background
Adult T-cell leukemia-lymphoma (ATL) is a peripheral T-cell tumor divided into acute, lymphoma and chronic forms with poor prognostic factors. Relapsed or refractory ATL remains a disease with a poorer prognosis. In ATL cells, EZH2 expression is elevated and methylated histones accumulate abnormally at about half of the gene locus.
EZH1 and EZH2 are methyltransferases that specifically methylate the 27 th lysine residue of Histone H3 (Histone H3 lysine 27 h3k27) and exhibit methyltransferase activity by forming a protein complex of PRC2 (Polycomb compressed complex 2). There are two types of PRC2 complexes, PRC2-EZH1 and PRC2-EZH2, whose catalytic subunits are EZH1 and EZH2, respectively. Both PRC2-EZH1 and PRC2-EZH2 can monomethylate, dimethylate and trimethylate H3K 27.
Inhibition of EZH2 alone leaves methylated histones intact, while inhibition of EZH1 and EZH2 removes abnormally accumulated methylated histones, significantly reducing the viability of ATL cells in ATL cell lines and ATL patients. Although the mechanism of action is not detailed, such drugs that inhibit EZH1 and EZH2 show stronger anti-ATL cell line proliferative activity in vitro test systems than EZH2 inhibitors. Trimethylation of H3K27 suppresses expression of tumor suppressor genes and differentiation-related genes, and the PRC2 complex is thought to play an important role in the development and progression of cancer.
Valetostanate tosylate (valemetastat Tosilate) is an oral anticancer drug developed by the first three co-located companies, the mesocultural name of valetostanate valemetastat Tosilate: (2R) -7-chloro-2- [ trans-4- (dimethylamino) cyclohexyl]-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl]-2,4-dimethyl-1,3-benzodioxy-5-carboxamide mono (4-methylbenzenesulfonate) of formula: c 26 H 34 ClN 3 O 4 ·C 7 H 8 O 3 S, molecular weight: 660.22 CAS registry number 1809336-93-3, having the chemical structure:
vaumestastat tosylate is a selective inhibitor of Enhancer of zeste homolog (EZH 1 and EZH 2), and is presumed to have an effect of inhibiting tumor growth by inhibiting the methylation activity of EZH1/2 and inhibiting the methylation of H3K27 and the like.
In a phase II clinical study of varemetastetasone tosylate in japan on patients with relapsed or refractory ATL: the main end-point reaction rate (95% CI) was 48.0% (27.8-68.7%). The response rate of the group patients is as follows: acute type 62.5% (10/16 cases), lymphoma type 16.7% (1/6 cases), chronic type 33.3% (1/3 cases) with poor prognostic factor; median progression-free survival (95% ci), 32.14 weeks (13.14 weeks to no estimate), disease control (95% ci) 88.0% (68.8-97.5%).
Documents CN201680044712 and CN201580014878 report the synthetic route 1 of valmestasol as follows:
step 1: the starting material methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate was reacted with tert-butyl N- (trans-4-ethynylcyclohexyl) carbamate to give the intermediate methyl (2 RS) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate, which was purified by silica gel column chromatography.
Step 2: the intermediate (2 RS) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid methyl ester from the above step was resolved by chiral column chromatography to give the intermediate (2R) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid methyl ester in 23% yield.
And step 3: the intermediate (2R) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid methyl ester from the above step was hydrolyzed with sodium hydroxide to give the intermediate (2R) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid.
And 4, step 4: amidation of the intermediate (2R) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid with the starting material 3- (aminomethyl) -4,6-dimethyl-1,2-dihydropyridin-2-one hydrochloride gave the intermediate tert-butyl N- [ trans-4- [ (2R) -7-chloro-5- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methylcarbamoyl ] -2,4-dimethyl-1,3-benzodioxol-2-yl ] cyclohexyl ] carbamate, which was purified by silica gel column chromatography.
And 5: deprotection of the intermediate tert-butyl N- [ trans-4- [ (2R) -7-chloro-5- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methylcarbamoyl ] -2,4-dimethyl-1,3-benzodioxol-2-yl ] cyclohexyl ] carbamate in hydrochloric acid as described above affords the intermediate (2R) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide.
And 6: the intermediate (2R) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxol-5-carboxamide from the above step is azomethylated with formaldehyde to give (2R) -7-chloro-2- [ trans-4- (dimethylamino) cyclohexyl ] -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxol-5-carboxamide (Valemetastat), which is purified by silica gel column chromatography.
The route has longer steps, the chiral column resolution yield adopted in the step 2 is only 23%, and the column chromatography purification is adopted in multiple steps, so that the industrialization is difficult.
The prior art document TW202216654a reports a new synthetic route to vatimestastat 2, as follows:
step 1: the initial raw material 3,4-2-hydroxy-2-methyl benzoic acid methyl ester reacts with sulfuryl chloride to obtain an intermediate 5-chloro-3,4-dihydroxy-2-methyl benzoic acid methyl ester;
step 2: the intermediate 5-chloro-3,4-dihydroxy-2-methylbenzoic acid methyl ester and N- (trans-4-ethynylcyclohexyl) carbamic acid tert-butyl ester react to obtain the intermediate (2 RS) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-formic acid methyl ester.
And 3, step 3: the intermediate (2 RS) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid methyl ester from the above step was hydrolyzed with sodium hydroxide to give the intermediate (2 RS) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid.
And 4, step 4: intermediate (2 RS) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid from the above step S-1-phenylethylamine was obtained as an intermediate S-1-phenylethylamine salt of (2R) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid by a resolving agent.
And 5: the S-1-phenylethylamine salt of the intermediate (2R) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid from the previous step was desalted, deprotected and azomethylated to give the intermediate (2R) -2- [ trans-4- (dimethylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid hydrochloride.
And 6: the intermediate (2R) -2- [ trans-4- (dimethylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid hydrochloride obtained in the above step is subjected to amidation reaction with the starting material 3- (aminomethyl) -4,6-dimethyl-1,2-dihydropyridin-2-one hydrochloride to obtain vatistal.
In the route 2, the raw material 3,4-2-hydroxy-2-methylbenzoate is used as a starting material, and the vatistal is synthesized through 6 steps, wherein the resolving agent is adopted in the step 4 for chiral resolution; after the resolution, firstly, the intermediate is subjected to nitrogen methylation reaction, and then the amide butt joint of the 3- (aminomethyl) -4,6-dimethyl-1,2-dihydropyridin-2-one hydrochloride is carried out, although the whole process does not use column chromatography for purification, the problems of long route and low yield still exist.
In summary, the synthetic route of valsartan reported in the prior art documents is long, the yield is low, and the accessibility of the raw material drugs is poor, so technical innovation of the synthetic process is necessary to improve the accessibility of the raw material drugs.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a preparation method of valacitrex.
The invention only needs 2 steps to react to obtain the intermediate (2R) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-formamide, and the intermediate and formaldehyde are subjected to nitrogen methylation reaction to obtain the valnemetastat.
The method comprises the following steps:
step 1, 5-chloro-N- ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -3,4-dihydroxy-2-methylbenzamide and N- (trans-4-ethynylcyclohexyl) carbamic acid tert-butyl ester are subjected to C-O cross coupling reaction in an aprotic solvent with a ruthenium metal compound and a phosphine ligand compound catalyst to obtain an intermediate state (2 RS) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide, and the deprotection group is subjected to obtain (2 RS) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-3556-zxft 3525-benzodioxole-5-carboxamide) methyl ] -3579-dihydroxy-5-carboxamide, and the group is deprotected to obtain (2 RS) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (3735 zxft 3-dimethyl-3535-3525-dimethyl-3556-dihydropyridine-3-yl) methyl ] -5383-5-benzodioxole-carboxamide;
step 2, (2 RS) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide is resolved to give the single configuration (2R) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide.
The route of the invention is different from a synthetic route 1 of the valsartan reported by patents CN201680044712 and CN201580014878 of the prior art and is also different from a synthetic route 2 of the valsartan reported by a patent TW202216654A of the prior art.
The key intermediate (2R) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-formamide is prepared by 2 steps of operation, and the valistat is obtained by 1 step of reaction. The method has the advantages of easily available raw materials, short route, safe and simple operation, high product purity, low cost and the like.
As for the specific process steps of the invention, the innovation points are as follows:
in the reaction of step 1 of the present invention, the ruthenium metal compound catalyst is dodecacarbonyltriruthenium, and other ruthenium complex catalysts, such as phenylmethylenebis (tricyclohexylphosphorus) dichlororuthenium (II), tris (triphenylphosphine) carbonyldihydroruthenium, bis (triphenylphosphine) cyclopentadienyl ruthenium chloride, were tried, and the effect of the co-catalysis of dodecacarbonyltriruthenium and the phosphine ligand compound could not be achieved.
In the step 1 reaction of the invention, the effect of the co-catalysis of the dodecacarbonyl triruthenium and the phosphine ligand compound is obviously better than that of the direct use of the ruthenium complex catalyst.
In the reaction of step 1 of the present invention, the phosphine ligand compound is selected from the group consisting of tri (o-tolyl) phosphine, tri (p-tolyl) phosphine, tri (m-tolyl) phosphine, tri (3-methoxyphenyl) phosphine, tri (2-methoxyphenyl) phosphine, tri (3-methoxyphenyl) phosphine, 5-di-t-butylphosphin-1 ',3',5 '-triphenyl-1'H- [1,4'] bipyrazole, preferably tri (o-tolyl) phosphine, 5-di-t-butylphosphin-1', 3',5' -triphenyl-1'H- [1,4' ] bipyrazole, particularly preferably tri (o-tolyl) phosphine.
In the present invention, the reaction of step 1 must be carried out in an aprotic solvent to minimize the generation of by-products, and in addition, the solvent is selected from the group consisting of high boiling solvents of toluene, xylene, dioxane, DMF, DMSO, N-methylpyrrolidone, and preferably toluene in consideration of the reaction temperature and the solubility characteristics to the materials, thereby controlling the reaction temperature and the solubility of the materials.
In the reaction of step 1 of the present invention, the N- (trans-4-ethynylcyclohexyl) carbamic acid tert-butyl ester is fed in excess, so that the generation of by-products can be avoided to the utmost extent, and the excess material can be removed by post-treatment extraction, but too much excess will increase the material cost. Through research, the feeding ratio is preferably controlled, and the molar feeding ratio of 5-chloro-N- ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -3,4-dihydroxy-2-methylbenzamide to N- (trans-4-ethynylcyclohexyl) carbamic acid tert-butyl ester is 1:1-1.5, preferably 1.1-1, and particularly preferably 1.2.
In the reaction of step 1 of the invention, the Liaoning metal compound catalyst is expensive, the activity is higher, and the optimization of the dosage can greatly reduce the production cost, and through research and exploration, the molar charge ratio of 5-chloro-N- ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -3,4-dihydroxy-2-methylbenzamide to Liaoning metal compound catalyst is 1. The phosphine ligand compound catalyst and the Liaoning metal compound catalyst are matched according to a molar ratio of 1:3 to form a compound to achieve the best catalytic effect, so that the molar charge ratio of the 5-chloro-N- ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -3,4-dihydroxy-2-methylbenzamide to the phosphine ligand compound catalyst is 1.
In the reaction of step 1 of the present invention, higher reaction temperature and longer reaction time can result in the generation of byproducts, and research has revealed that the conditions for optimizing the reaction include: the temperature of the C-O cross-coupling reaction stage is 80-100 ℃, and the stirring reaction is preferably carried out at 90-100 ℃ for 5-7 hours. The temperature of the deprotection reaction stage is 20-30 ℃, and the reaction is stirred for 1-2 hours, so that the generation of byproducts can be reduced to the maximum extent.
In the invention, in the step 2, (2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-formamide is resolved into a single R configuration by chiral acid resolution or chiral column resolution, wherein the chiral acid resolution yield is high, and the method is suitable for industrialization and is preferred.
In step 2 of the present invention, the chiral acid resolving agent of (2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide is selected from D-tartaric acid, D-camphoric acid, D-dibenzoyltartaric acid, D-mandelic acid, wherein the optical purity of the resolution of D-tartaric acid and D-camphoric acid is higher, preferably, and the yield of D-tartaric acid is higher as a particular preference.
In the preparation method of step 2 of the present invention, excessive chiral acid resolving agent causes precipitation of S configuration, which affects optical purity, and too little chiral acid resolving agent causes lower yield, and it is confirmed through research and investigation that the molar ratio of (2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide to chiral acid resolving agent is 1.
In the preparation method of step 2 in the present invention, (2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide is resolved by chiral acid in alcoholic solvent selected from methanol, absolute ethanol, isopropanol, wherein the absolute ethanol yield is highest and the optical purity of the objective product is high, preferably.
In the preparation method of the step 2 in the invention, after (2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-formamide and chiral acid in the step 2 are refluxed and dissolved in an alcohol solvent to form a salt, standing and naturally cooling are firstly carried out to 45-60 ℃, preferably 50-55 ℃, chiral acid salt seed crystals of the R configuration target product are added, then standing and naturally cooling and crystallizing are carried out continuously, and the seed crystals are added to ensure the optical purity of the target product.
Therefore, the invention finds a synthetic method of the valsartan isoproxil with shorter route, lower cost and more industrial potential by the new synthetic route design of the valsartan intermediate (2R) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-formamide and the optimization of the synthetic method, and can benefit from the synthetic method.
The novel synthesis and advantages of the intermediate (2R) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide in Valetastax, will be further illustrated in conjunction with examples 1-5 and comparative examples. The intermediate, (2R) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide may be prepared to yield Valetastax by reference to Steps 1-6 of example 1 in the comparative patent CN 201680044712.
Drawings
FIG. 1: synthesis route of Valetostastat
The specific implementation method comprises the following steps:
the technical solutions in the embodiments of the present invention will be described in detail below with reference to the embodiments of the present invention, but the following embodiments are only for understanding the present invention and do not limit the present invention, and the present invention can be implemented in various ways as defined and covered by the claims.
The following are examples of the present invention:
example 1 (2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide
Adding 5-chloro-N- ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -3,4-dihydroxy-2-methylbenzamide (33.7g, 0.1mol), tert-butyl N- (trans-4-ethynylcyclohexyl) carbamate (26.8g, 0.12mol), triruthenium dodecacarbonyl (6.4g, 0.01mol) and tris (o-tolyl) phosphine (9.2g, 0.3mol) to 400ml of toluene under a nitrogen atmosphere, heating to reflux reaction for 6h, filtering while hot, evaporating the solvent to dryness in the filtrate under reduced pressure, adding dichloromethane 200ml to the residue, adding 200ml of a 1mol/L sodium carbonate solution for washing and separating, washing the organic phase twice with water (200 ml/time), adding anhydrous sodium sulfate 10g of the organic phase for drying for 2h, filtering, and evaporating the solvent to dryness under reduced pressure;
adding methanol 150ml and 4M hydrochloric acid solution 200ml into residue, stirring and reacting at 20-30 deg.C for 1.5h, adding 100ml water into reaction solution, extracting twice with ethyl acetate (150 ml/time), adding dichloromethane 300ml, adjusting pH to 7-8 with saturated sodium carbonate solution under stirring, separating, washing organic phase twice with water (200 ml/time), adding anhydrous sodium sulfate 10g into organic phase, drying for 2h, filtering, evaporating solvent from filtrate under reduced pressure, adding n-hexane 150ml into residue, stirring and dispersing, filtering, adding n-hexane 150ml into residue, stirring and dispersingOven drying to give the title product (2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide (42.8 g, yield 94%, purity 99.1%). Ms M/z 460.2 (M + 1). 1 H NMR(300MHz d 6 -DMSO)：δ1.39-1.75(m，8H)，1.72(d，3H),2.26(s，3H),2.32(s，3H)，2.34(t，1H)，2.43(d，3H),3.87(s，2H),5.56(s，1H),7.58(s，1H)，8.45(s，1H)。
Example 2 (2R) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide
Adding (2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide (34.5g, 0.075mol) into 140ml of absolute ethanol, refluxing for dissolution, adding D-tartaric acid (5.6g, 37.5mmol) and continuing to reflux until complete dissolution, stopping stirring, standing for natural cooling to 50-55 ℃, adding 0.5g of target product D-tartaric acid seed crystal (ee value and purity are more than or equal to 99%), continuing to naturally cooling to room temperature, standing for crystallization for 3-4h, stirring and filtering, adding filter cake into 100ml of sodium carbonate and 100ml of dichloromethane, stirring for dissolution, and dropwise adding saturated sodium carbonate solution to ph7-8; the organic phase was washed 2 more times with water (50 ml/time), dried over 2.5g anhydrous sodium sulfate for 2h, filtered, the filtrate was concentrated to dryness under reduced pressure, the residue was stirred with 50ml N-hexane and dispersed, filtered and the title product (2R) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid (15.5 g, yield 45%, ee value 98.9%) was dried.
Example 3 (2R) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide
Adding (2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide (34.5g, 0.075mol) into 140ml of absolute ethanol, refluxing for dissolution, adding D-camphoric acid (7.5g, 37.5mmol) and continuing to reflux until complete dissolution, stopping stirring, standing for natural cooling to 50-55 ℃, adding a target product D-camphorate seed crystal (ee value and purity are more than or equal to 99%) 0.5g, continuing to naturally cool to room temperature, standing for crystallization for 3-4h, stirring for filtration, adding a filter cake into 100ml of sodium carbonate and 100ml of dichloromethane and stirring for dissolution, and dropwise adding a saturated solution to ph7-8; the organic phase was washed 2 more times with water (50 ml/time), dried for 2h over 2.5g anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was dispersed with 50ml N-hexane under stirring, filtered and dried to give the title product (2R) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide (13.8 g, yield 40%, ee value 99.2%).
Example 4 (2R) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide
(2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide 1.5g was isolated using the following chiral half preparative chromatography:
a chromatographic column: the amount of the large xylonite is that of the xylonite,
OD-H 5μm,250mm×20mm
elution solvent n-hexane: ethanol =95
Temperature: 25 deg.C
Product peak: the second main peak was separated by chiral column and the collected solution was dried under reduced pressure to obtain about 0.6g of the product (yield 40%, ee value 99.5%).
Example 5 Varmestastat
(2R) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide (11.5g, 25mmol), methanol (140 mL) was added to a three-necked flask, 37% aqueous formaldehyde (4.3g, 52.5mmol) was added, stirring was performed at room temperature for 15 minutes, sodium triacetoxyborohydride (26.5g, 0.125mol) was added, followed by stirring at room temperature for 16 hours. After the reaction, the reaction mixture was neutralized with 1M aqueous sodium hydroxide solution, 200ml of chloroform was added for extraction, the organic phase was washed with 200ml of water and then 100ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, 30ml of n-hexane was added to the residue, stirred and dispersed, filtered, the filter cake was recrystallized from anhydrous ethanol (30 ml) -water (30 ml), filtered and dried to obtain vatistal (11.4 g, yield 93%, purity 99.83%).
Comparative example:
the process for synthesizing valistastat in example 1 in chinese patent CN201680044712 has the following route:
comparative document CN201080031144 example 1 of synthetic vatistal is as follows:
example 1: (2R) -7-chloro-2- [ trans-4- (dimethylamino) cyclohexyl ] -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide (Valetostat)
(step 1-1) methyl 2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate
To a solution of methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate (1.00g, 4.62mmol) and tert-butyl N- (trans-4-ethynylcyclohexyl) carbamate (1.55g, 6.93mmol) in toluene (50 mL) were added triruthenium dodecacarbonyl (0) (0.0738g, 0.115mmol) and 5- (di-tert-butylphosphino) -1',3',5' -triphenyl-1'H- [1,4' ] bipyrazole (0.175g, 0.346mmol), and the resulting mixture was stirred at 120 ℃ for 1 hour under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off under reduced pressure, and the thus-obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate =100 to 80.
(step 1-2) (2R) -2- [ trans-4- (tert-Butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid methyl ester
The various enantiomers were isolated from methyl 2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate synthesized in step 1-1 under the following conditions:
column: daicel Corporation, CHIRALCEL OZ-H4.6 mm ID x 250mm L
Eluting solvent: n-hexane: ethanol =98
Flow rate: 1.00mL/min
Temperature: 25 deg.C
First peak: 10.7min ([ alpha ] D20= -18.3 (C =0.92, chloroform))
Second peak: 11.7min ([ α ] D20= +18.3 (C =0.96, chloroform)).
In the following step, the second peak separated by using a chiral column for separation was used.
(Steps 1-3) (2R) -2- [ trans-4- (tert-Butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid
To methyl (2R) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate (second peak, 0.234g, 0.532mmol) isolated in step 1-2, tetrahydrofuran (3 mL) and methanol (1.5 mL) were added, and to the resultant was further added a 1M aqueous sodium hydroxide solution (1.33mL, 1.33mmol), followed by stirring at room temperature for 16 hours. After completion of the reaction, 1M hydrochloric acid (1.33ml, 1.33mmol) was added thereto for neutralization, and methylene chloride was further added thereto for extraction. The organic layer thus obtained was concentrated under reduced pressure to obtain the title compound (0.227g, 0.532mmol,100% yield).
(step 1-4) N- [ trans-4- [ (2R) -7-chloro-5- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methylcarbamoyl ] -2,4-dimethyl-1,3-benzodioxol-2-yl ] cyclohexyl ] carbamic acid tert-butyl ester
To a solution of (2R) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid (0.227g, 0.532mmol) synthesized in steps 1-3 in dimethylformamide (5 mL) was added 3- (aminomethyl) -4,6-dimethyl-1,2-dihydropyridin-2-one hydrochloride (0.116g, 0.586 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.122g, 0.639mmol), 1-hydroxy-7-azabenzotriazole (0.0869g, 0.639mmol), and N, N-diisopropylethylamine (0.223mL, 1.289mmol), and the resultant was stirred under nitrogen atmosphere at room temperature for 1.5 hours. After completion of the reaction, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the resultant was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in chloroform and purified by silica gel column chromatography (chloroform: methanol = 100.
(Steps 1-5) (2R) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide
N- [ trans-4- [ (2R) -7-chloro-5- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methylcarbamoyl ] -2,4-dimethyl-1,3-benzodioxol-2-yl ] cyclohexyl ] carbamic acid tert-butyl ester synthesized in steps 1-4 (0.298g, 0.532mmol) was dissolved in methanol (1.3 mL), and 4M hydrochloric acid-1,4-dioxane solution (1.33mL, 5.32mmol) was added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added thereto for neutralization, and 20% methanol-chloroform was used for extraction. The resulting organic layer was washed with a saturated saline solution, dried over sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (0.241g, 0.524mmol,98% yield).
(Steps 1-6) (2R) -7-chloro-2- [ trans-4- (dimethylamino) cyclohexyl ] -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide (Valetostat)
(2R) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide (17.0 g,36.9 mmol) synthesized in steps 1 to 5 was dissolved in methanol (200 mL), 37% aqueous formaldehyde solution (6.29g, 77.5 mmol) was added thereto, the resultant was stirred at room temperature for 10 minutes, and sodium triacetoxyborohydride (34.2g, 129mmol) was added thereto, followed by stirring at room temperature for 16 hours. After completion of the reaction, the resultant was neutralized with 1M aqueous sodium hydroxide solution, and used for extraction with 20% methanol-chloroform. The resulting organic layer was washed with a saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure, and the thus-obtained residue was purified by basic silica gel column chromatography (ethyl acetate: methanol =100:0 to 96.
Compared with the synthetic method of the vatistal provided by the comparative example, the synthetic method of the vatistal provided by the embodiments 1-5 of the invention has the advantages of short route, high yield, high chemical purity of the obtained vatistal, reduced health damage to production operators due to the short route, and more environment-friendly effect.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of a medicine of vatistal for treating adult T cell leukemia lymphoma is characterized by comprising the following steps:
the intermediate is (2R) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide.
2. The process according to claim 1, wherein step 1, 5-chloro-N- ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -3,4-dihydroxy-2-methylbenzamide and tert-butyl N- (trans-4-ethynylcyclohexyl) carbamate are subjected to a C-O cross-coupling reaction to give intermediate state (2 RS) -2- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide, which is deprotected to give (2 RS) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-3856-zxft 5256-benzodioxole-5-carboxamide) methyl ] -5383 zxft 5229-methyl-5-dihydrobenzoxaft 5383;
step 2, (2 RS) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide is resolved to give the single configuration (2R) -2- (trans-4-aminocyclohexyl) -7-chloro-N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide.
3. The preparation method according to claim 1, wherein the metal catalyst in the step 1 reaction is dodecacarbonyl triruthenium; and/or;
the molar charge ratio of 5-chloro-N- ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -3,4-dihydroxy-2-methylbenzamide to triruthenium dodecacarbonyl catalyst in the step 1 reaction is 1.
4. The process according to claim 1, wherein the ligand catalyst in the step 1 reaction is a phosphine ligand compound selected from the group consisting of tri (o-tolyl) phosphine, tri (p-tolyl) phosphine, tri (m-tolyl) phosphine, tri (3-methoxyphenyl) phosphine, tri (2-methoxyphenyl) phosphine, tri (3-methoxyphenyl) phosphine, 5-di-t-butylphosphine-1 ',3',5 '-triphenyl-1'H- [1,4'] bipyrazole, preferably tri (o-tolyl) phosphine, 5-di-t-butylphosphine-1', 3',5' -triphenyl-1'H- [1,4' ] bipyrazole, particularly preferably tri (o-tolyl) phosphine.
5. The process according to claim 1, wherein the reaction of step 1 is carried out in an aprotic solvent selected from the group consisting of toluene, xylene, dioxane, DMF, DMSO, N-methylpyrrolidone, preferably toluene.
6. The preparation method according to claim 1, wherein the molar charge ratio of 5-chloro-N- ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -3,4-dihydroxy-2-methylbenzamide and tert-butyl N- (trans-4-ethynylcyclohexyl) carbamate in the step 1 reaction is 1:1-1.5, preferably 1.1-1.3, particularly preferably 1.
7. The preparation method according to claims 1 and 3, characterized in that the molar charge ratio of 5-chloro-N- ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -3,4-dihydroxy-2-methylbenzamide and phosphine ligand compound catalyst in the step 1 reaction is 1.
8. The synthesis method according to claim 1, wherein the reaction conditions of the step 1 comprise: the temperature of the C-O cross coupling reaction stage is 80-100 ℃, and the stirring reaction is preferably carried out for 5-7 hours at 90-100 ℃. The temperature of the deprotection reaction stage is 20-30 ℃, and the stirring reaction is carried out for 1-2 hours.
9. The process according to claim 1, wherein the resolution of (2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide in step 2 into a single R configuration is a chiral acid resolution or a chiral column resolution, preferably a chiral acid resolution.
10. The production method according to claim 1 to 9,
the chiral acid resolving agent of (2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide in step 2 is selected from D-tartaric acid, D-camphoric acid, D-dibenzoyltartaric acid, D-mandelic acid, preferably D-tartaric acid or D-camphoric acid, particularly preferably D-tartaric acid; and/or;
the molar ratio of (2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide to chiral acid resolving agent in step 2 is from 1; and, or;
in the step 2, (2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-carboxamide is resolved by chiral acid in alcoholic solvent, the alcoholic solvent is selected from methanol, absolute ethanol, isopropanol, and preferably absolute ethanol; and/or;
in the step 2, (2 RS) -7-chloro-2- (trans-4-aminocyclohexyl) -N- [ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ] -2,4-dimethyl-1,3-benzodioxole-5-formamide and chiral acid are refluxed to form salt and dissolved in an alcohol solvent, and then the mixture is stood and naturally cooled to 45-60 ℃, preferably 50-55 ℃, chiral acid salt seed crystals of the high-purity R configuration target product are added, and then the mixture is stood and naturally cooled to crystallize.
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