CN104610133A - Method for synthesizing novel anticancer medicine entinostat - Google Patents
Method for synthesizing novel anticancer medicine entinostat Download PDFInfo
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- CN104610133A CN104610133A CN201510039804.7A CN201510039804A CN104610133A CN 104610133 A CN104610133 A CN 104610133A CN 201510039804 A CN201510039804 A CN 201510039804A CN 104610133 A CN104610133 A CN 104610133A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
Abstract
The invention provides a method for synthesizing a novel anticancer medicine entinostat. The method comprises the following steps: by taking pyridine-3-methanol as a raw material, performing carbon chain elongation reaction, performing amidation reaction with 4-(aminomethyl)benzoic acid under the action of a catalyst so as to obtain a compound 1, further carrying out amidation reaction between the compound 1 and o-phenylenediamine under the action of the catalyst so as to obtain a crude product, and performing acid soluble alkali-out refining on the crude product, so as to obtain a product which meets the quality standard. The method has the advantages that firstly, the method is simple and convenient, that is, raw materials are easy to obtain, and the process is simple in step, gentle and controllable in unit reaction, simple and feasible in operation and good in repeatability; secondly, the method is applicable to industrial production, that is, the process is simple and short in route, gentle and controllable in reaction condition and applicable to industrial production; thirdly, the product is stable and high in purity, and on the basis that the product is not refined, the purity of the product can be higher than 99%; fourthly, reagents and solvents are environment-friendly, can be easily purchased from the market, and are applicable to later industrialization requirements.
Description
Technical field
The present invention relates to the synthetic method of a kind of PTS grace for Nuo Te, belong to technical field of medicine synthesis.
Background technology
(grace is for Nuo Te for carboxylamine 3-pyridylmethyl ester for N-[[4-[[(2-aminophenyl) is amino] formyl] phenyl] methyl], Entinostat, MS-275) be a kind of oral I class hdac inhibitor of novelty that U.S. Syndax Pharma develops, present stage, indication was mammary cancer, be in three phase clinical stages at present, obtain in September, 2013 medicine that FDA is approved as breakthrough treatment simultaneously, because of its obvious security and validity, no matter as single medicament or the combination with existing target therapeutic agent, it is all made to be different from other histon deacetylase (HDAC)s (HDAC) inhibitor.In normal cell, this enzyme plays the keying action of controlling gene expression by changing chromatinic structure, and this enzyme is understood overexpression and caused the reversible resistance based on epigenetics in tumour cell.Grace optionally for HDAC hypotype maximally related with oncobiology, can make the expression normalizing of gene out of control in tumour cell for Nuo Te, thus recovers the sensitivity to other target therapeutic agents.Grace is first hdac inhibitor obtaining positive findings in mammary cancer II phase randomized clinical control study for Nuo Te, is also a unique hdac inhibitor being in mammary cancer late phase clinical and developing.
Record and report for the synthetic method of Nuo Te is also relevant in patent and document about grace at present, in view of its distinctive curative effect and market potential are worth, need to develop a kind of be applicable to suitability for industrialized production preferably prepare the method for grace for Nuo Te.
Summary of the invention
In order to overcome the deficiencies in the prior art part, the invention provides the synthetic method of a kind of new type anticancer new drug grace for Nuo Te.
PTS grace of the present invention is for the preparation method of Nuo Te, and the method comprises the steps:
1. with pyridine-3-methyl alcohol for starting raw material, first extend reagent to carry out carbochain and extend with carbochain and react, after carbochain extends, under catalyst action, carry out amidate action with Aminomethylbenzoic Acid and obtain compound 1, then crystallization is carried out, the consumption mol ratio that described starting raw material and carbochain extend reagent is 1:(1 ~ 2), the consumption mol ratio of starting raw material and Aminomethylbenzoic Acid is 1:(1 ~ 2), the consumption mol ratio of starting raw material and catalyzer is 1:(1 ~ 2), the pH value that during crystallization reaction, system controls is 4 ~ 5, and temperature of reaction-10 DEG C is to 60 DEG C;
2. there is amidate action and obtain compound 2 in compound 1 and O-Phenylene Diamine under catalyst action, namely grace is for the extraordinarily thick product of promise, described compound 1 is 1:(3 ~ 6 with the consumption mol ratio of O-Phenylene Diamine), compound 1 is 1:(1 ~ 4 with the consumption mol ratio of catalyzer), temperature of reaction-10 DEG C is to 60 DEG C;
3. compound 2 is analysed through acid-soluble alkali, and the refining grace that obtains is for the special fine work of promise, and controlling system pH when compound 2 dissolves is 2 ~ 3, and the pH value that during crystallization reaction, system controls is 8, and temperature of reaction is-10 DEG C to 60 DEG C.
Wherein,
Step 1. in, in carbochain reaction of propagation, reaction reagent is N, N ,-carbonyl dimidazoles (CDI); Temperature of reaction is-10 DEG C to 40 DEG C; Solvent is tetrahydrofuran (THF), dimethyl formamide, dimethyl sulfoxide (DMSO), one or more mixture of acetonitrile.The catalyzer of carbochain reaction of propagation is N, N-diisopropylethylamine, triethylamine, pyridine, O-benzotriazole-N, one or more mixture in N, N', N'-tetramethyl-urea Tetrafluoroboric acid (TBTU), DMAP (DMAP), N-methylmorpholine.Preferably, step 1. in, the catalyzer of carbochain reaction of propagation is DIPEA, triethylamine, DMAP (DMAP), N-methylmorpholine, and solvent is dimethyl formamide or tetrahydrofuran (THF).
Step 2. in, catalytic reagent is N, N'-carbonyl dimidazoles (CDI), 2-(7-azo benzotriazole)-N, N, one or more mixture in N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-1-base-oxygen base tripyrrole Wan Ji Phosphonium phosphofluoric acid (PyBOP), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), I-hydroxybenzotriazole (HOBT), methylsulfonic acid; Temperature of reaction is-10 DEG C to 40 DEG C; Solvent is tetrahydrofuran (THF), dimethyl formamide, dimethyl sulfoxide (DMSO), one or more mixture of acetonitrile.Preferably, step 2. in, catalyzer is N, N'-carbonyl dimidazoles (CDI), benzotriazole-1-base-oxygen base tripyrrole Wan Ji Phosphonium phosphofluoric acid (PyBOP), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), I-hydroxybenzotriazole (HOBT), methylsulfonic acid, solvent is dimethyl formamide or acetonitrile.
Step 3. in, grace is 1:(5-15 for the mass volume ratio (gram: milliliter) of the extraordinarily thick product of promise and water), temperature of reaction is-10 DEG C to 30 DEG C.
Concrete synthetic route of the present invention is as follows:
New type anticancer new drug grace of the present invention is as follows for the synthetic method principle of Nuo Te: with pyridine-3-methyl alcohol for raw material, extend through carbochain and with Aminomethylbenzoic Acid, amidation occurs under catalyst action after reaction and send out and should obtain compound 1, compound 1 carries out that amidate action occurs under catalyst action again and obtains thick product with O-Phenylene Diamine, crude product through acid-soluble alkali analyse refining after obtain meeting the product of quality standard.
The invention has the advantages that:
1, method is easy.Starting material are easy to get, and involved processing step is simple, and unit process is gentle, easy to operation, favorable reproducibility, involved in the present invention to intermediate all do not need refiningly to be directly used in next step and to feed intake;
2, suitability for industrialized production is applicable to.Present invention process route is brief, and reaction conditions is gentle, controlled, is very applicable to suitability for industrialized production;
3, product is stable, product purity is high.On the basis of not refining product, product purity reaches more than 99%.
4, adopt reagent and solvent environmentally friendly, and be easy to from market buy, meet industrialization demand in the future.
Accompanying drawing explanation
Fig. 1 is under condition of the present invention, and the grace prepared by embodiment 1 is for the special IR collection of illustrative plates of promise.
Embodiment
Following example, just for illustration of the present invention, is not for limiting the present invention.
Embodiment 1 grace is for the synthesis of Nuo Te
1. the synthesis of compound 1
N is added in 500ml reaction flask, N '-carbonyl dimidazoles 75g (462.5mmol), tetrahydrofuran (THF) 100ml, stir, at room temperature (10 ~ 20 DEG C) drip the 3-piconol (25.2g prepared, tetrahydrofuran solution 50ml 231mmol), after dropping terminates, at room temperature (10 ~ 20 DEG C) react 6h.System is cooled to about 0 DEG C, temperature control about 0 DEG C adds Aminomethylbenzoic Acid 34.9g (231mmol), and after stirring 30min, temperature control drips N at about 0 DEG C, N-diisopropylethylamine 59.7g (462.5mmol), drips 0 ~ 10 DEG C of reaction 8h after terminating.Reaction terminates rear temperature control 0 ~ 20 DEG C and drips concentrated hydrochloric acid regulation system pH=4 ~ 5, after adjustment, at 0 ~ 20 DEG C, stirs 4h.Filter, filter cake 500ml purified water is washed at twice, after draining, and wet product 40 ~ 50 DEG C of forced air drying 8h.Obtain faint yellow solid compound Isosorbide-5-Nitrae 9.5g, yield 74.9%.Prepared compound 1
1hNMR,
13cNMR chemistry place value is as follows:
1H NMR(DMSO-d6,400MHz,ppm):δ4.28(d,J＝5.9Hz,2H)，δ4.87(s,2H)，δ5.10(s,2H)，δ7.37(d,J＝7.9Hz,2H)，δ7.41(dd,J＝4.9Hz、7.9Hz,1H)，δ7.79(d.br,J＝7.4Hz,1H)，δ7.93(d,J＝7.9Hz,1H)，δ7.93-7.97(m,1H)，δ8.53(d.br,J＝4.9Hz,1H)，δ8.60(s,1H)，δ9.60(s,1H)，δ11.60(s,1H)
13CNMR(DMSO-d6,400MHz,ppm):δ43.81，δ63.43，δ116.32，δ123.56，δ126.60，，δ127.99，δ132.84，δ133.42，δ135.86，δ143.24，δ143.29，δ149.27，δ149.30，δ156.42，δ167.14
2. the synthesis of compound 2
42g (146.7mmol) compound 1, dimethyl formamide 100ml is dropped in 500ml reaction flask, at room temperature (10 ~ 20 DEG C) add N, N '-carbonyl dimidazoles 35.7g (220mmol), at room temperature (10 ~ 20 DEG C) stirring reaction 2h.System is cooled to about 0 DEG C, control temperature drips the dimethyl formamide solution 150ml of the O-Phenylene Diamine (47.6g, 440.1mmol) prepared at about 0 DEG C, drips and finishes, and about 0 DEG C is stirred 30min.Control temperature drips methylsulfonic acid 28.2g (293.4mmol) at about 0 DEG C, drips and finishes, 0 ~ 20 DEG C of reaction 8h.After reaction terminates, reaction solution is poured in 2500ml purified water, at room temperature (10 ~ 20 DEG C) making beating 12h.Filter, filter cake 800ml purified water is washed at twice, and after draining, wet product 40 ~ 50 DEG C of vacuum-drying 20h, obtain faint yellow solid compound 2,48g, yield 87%.
3. grace is for the synthesis of Nuo Te
In 1L reaction flask, add 40g compound 2, purified water 400ml, stir evenly and system is cooled to 0 ~ 10 DEG C simultaneously, temperature control 0 ~ 10 DEG C drips 10% hydrochloric acid, is dissolved to clearly for standard with system, stirs half an hour.Temperature control 0 ~ 10 DEG C drips 10% sodium hydroxide solution, regulates pH=8, and after adjustment, 0 ~ 10 DEG C is stirred 2h.Filter, filter cake purifies moisture three times washing with 600ml, and after draining, wet product 40 ~ 50 DEG C of vacuum-drying 20h, obtain off-white color solid grace for Nuo Te, 24.8g, yield 62%.Under the present embodiment condition, prepared grace is for Nuo Te
1hNMR,
13cNMR chemical displacement value is as follows:
1H NMR(DMSO-d6,400MHz,ppm):δ4.28(d,J＝5.9Hz,2H)，δ4.87(s,2H)，δ5.10(s,2H)，δ6.60(t.br,J＝6.9Hz,1H)，δ6.78(d.br,J＝6.9Hz,1H)，δ6.97(tbr,J＝6.9Hz,1H)，δ7.17(d.br,J＝6.9Hz,1H)，δ7.37(d,J＝7.9Hz,2H)，δ7.41(dd,J＝4.9Hz、7.9Hz,1H)，δ7.79(d.br,J＝7.4Hz,1H)，δ7.93(d,J＝7.9Hz,2H)，δ7.93-7.97(m,1H)，δ8.53(d.br,J＝4.9Hz,1H)，δ8.60(s,1H)，δ9.60(s,1H)
13CNMR(DMSO-d6,400MHz,ppm):δ43.81，δ63.43，δ116.32，δ116.45，δ123.56，δ123.66，δ126.60，δ126.80，δ126.92，δ127.99，δ132.84，δ133.42，δ135.86，δ143.24，δ143.29，δ149.27，δ149.30，δ156.42，δ165.29
Grace obtained under embodiment 1 condition is shown in accompanying drawing for the special IR collection of illustrative plates of promise.
Embodiment 2 grace is for the synthesis of Nuo Te
1. the synthesis of compound 1
N is added in 500ml reaction flask, N '-carbonyl dimidazoles 37.5g (231mmol), tetrahydrofuran (THF) 200ml, stir, at room temperature (10 ~ 20 DEG C) drip the 3-piconol (25.2g prepared, tetrahydrofuran solution 60ml 231mmol), after dropping terminates, at room temperature (10 ~ 20 DEG C) react 6h.System is cooled to about 0 DEG C, temperature control about 0 DEG C adds Aminomethylbenzoic Acid 69.8g (462mmol), and after stirring 30min, temperature control drips triethylamine 35.1g (346.5mmol) at about 0 DEG C, drips 0 ~ 10 DEG C of reaction 8h after terminating.Reaction terminates rear temperature control 0 ~ 20 DEG C and drips concentrated hydrochloric acid regulation system pH=4 ~ 5, after adjustment, at 0 ~ 20 DEG C, stirs 4h.Filter, filter cake 500ml purified water is washed at twice, after draining, and wet product 40 ~ 50 DEG C of forced air drying 8h.Obtain faint yellow solid compound Isosorbide-5-Nitrae 8.6g, yield 73.5%.Compound 1 obtained under the present embodiment
1hNMR,
13cNMR chemical displacement value is with embodiment 1.
2. the synthesis of compound 2
42g (146.7mmol) compound 1, acetonitrile 300ml is dropped in 1L reaction flask, at room temperature (10 ~ 20 DEG C) add N, N '-carbonyl dimidazoles 35.7g (220mmol), at room temperature (10 ~ 20 DEG C) stirring reaction 2h.System is cooled to about 0 DEG C, control temperature drips the acetonitrile solution 150ml of the O-Phenylene Diamine (63.5g, 586.8mmol) prepared at about 0 DEG C, drips and finishes, and about 0 DEG C is stirred 30min.Control temperature drips methylsulfonic acid 35.2g (366.8mmol) at about 0 DEG C, drips and finishes, 0 ~ 20 DEG C of reaction 8h.After reaction terminates, reaction solution is poured in 2500ml purified water, at room temperature (10 ~ 20 DEG C) making beating 12h.Filter, filter cake 800ml purified water is washed at twice, and after draining, wet product 40 ~ 50 DEG C of vacuum-drying 20h, obtain faint yellow solid compound 2,49.2g, yield 89.2%.
3. grace is for the synthesis of Nuo Te
In 1L reaction flask, add 40g compound 2, purified water 200ml, stir evenly and system is cooled to 0 ~ 10 DEG C simultaneously, temperature control 0 ~ 10 DEG C drips 10% hydrochloric acid, is dissolved to clearly for standard with system, stirs half an hour.Temperature control 0 ~ 10 DEG C drips 10% sodium hydroxide solution, regulates pH=8, and after adjustment, 0 ~ 10 DEG C is stirred 2h.Filter, filter cake purifies moisture three times washing with 600ml, and after draining, wet product 40 ~ 50 DEG C of vacuum-drying 20h, obtain off-white color solid grace for Nuo Te, 25.3g, yield 63.2%.Grace obtained under the present embodiment is for Nuo Te
1hNMR,
13cNMR chemical displacement value is with embodiment 1.
Embodiment 3 grace is for the synthesis of Nuo Te
1. the synthesis of compound 1
N is added in 500ml reaction flask, N '-carbonyl dimidazoles 56.2g (346.5mmol), dimethyl formamide 150ml, stir, at room temperature (10 ~ 20 DEG C) drip the 3-piconol (25.2g prepared, dimethyl formamide solution 50ml 231mmol), after dropping terminates, at room temperature (10 ~ 20 DEG C) react 6h.System is cooled to about 0 DEG C, temperature control about 0 DEG C adds Aminomethylbenzoic Acid 52.4g (346.5mmol), after stirring 30min, temperature control drips N-methylmorpholine 23.5g (231mmol) at about 0 DEG C, drips 0 ~ 10 DEG C of reaction 8h after terminating.Reaction terminates rear temperature control 0 ~ 20 DEG C and drips concentrated hydrochloric acid regulation system pH=4 ~ 5, after adjustment, at 0 ~ 20 DEG C, stirs 4h.Filter, filter cake 500ml purified water is washed at twice, after draining, and wet product 40 ~ 50 DEG C of forced air drying 8h.Obtain faint yellow solid compound 1,50.2g, yield 76%.Compound 1 obtained under the present embodiment
1hNMR,
13cNMR chemical displacement value is with embodiment 1.
2. the synthesis of compound 2
42g (146.7mmol) compound 1, dimethyl formamide 100ml is dropped in 1L reaction flask, system is cooled to about 0 DEG C, control temperature drips the dimethyl formamide solution 100ml of benzotriazole-1-base-oxygen base tripyrrole Wan Ji Phosphonium phosphofluoric acid (PyBOP) 76.3g (146.7mmol) at about 0 DEG C, about 0 DEG C is stirred 0.5h, drip the O-Phenylene Diamine (95.2g prepared, dimethyl formamide solution 200ml 880.2mmol), drip and finish, 0 ~ 20 DEG C of reaction 4h.After reaction terminates, reaction solution is poured in 3200ml purified water, at room temperature (10 ~ 20 DEG C) making beating 12h.Filter, filter cake 800ml purified water is washed at twice, and after draining, wet product 40 ~ 50 DEG C of vacuum-drying 20h, obtain faint yellow solid compound 2,49.6g, yield 90%.
3. grace is for the synthesis of Nuo Te
In 1L reaction flask, add 40g compound 2, purified water 600ml, stir evenly and system is cooled to 0 ~ 10 DEG C simultaneously, temperature control 0 ~ 10 DEG C drips 10% hydrochloric acid, is dissolved to clearly for standard with system, stirs half an hour.Temperature control 0 ~ 10 DEG C drips 10% sodium hydroxide solution, regulates pH=8, and after adjustment, 0 ~ 10 DEG C is stirred 2h.Filter, filter cake purifies moisture three times washing with 600ml, and after draining, wet product 40 ~ 50 DEG C of vacuum-drying 20h, obtain off-white color solid grace for Nuo Te, 24.2g, yield 60.5%.Grace obtained under the present embodiment is for Nuo Te
1hNMR,
13cNMR chemical displacement value is with embodiment 1.
Embodiment 4 grace is for the synthesis of Nuo Te
1. the synthesis of compound 1
N is added in 500ml reaction flask, N '-carbonyl dimidazoles 75g (462.5mmol), tetrahydrofuran (THF) 150ml, stir, at room temperature (10 ~ 20 DEG C) drip the 3-piconol (25.2g prepared, tetrahydrofuran solution 50ml 231mmol), after dropping terminates, at room temperature (10 ~ 20 DEG C) react 6h.System is cooled to about 0 DEG C, temperature control about 0 DEG C adds Aminomethylbenzoic Acid 34.9g (231mmol), after stirring 30min, temperature control drips the tetrahydrofuran solution 100ml of DMAP 42.3g (346.5mmol) at about 0 DEG C, drips 0 ~ 10 DEG C of reaction 8h after terminating.Reaction terminates rear temperature control 0 ~ 20 DEG C and drips concentrated hydrochloric acid regulation system pH=4 ~ 5, after adjustment, at 0 ~ 20 DEG C, stirs 4h.Filter, filter cake 500ml purified water is washed at twice, after draining, and wet product 40 ~ 50 DEG C of forced air drying 8h.Obtain faint yellow solid compound 1,52g, yield 78.6%.Compound 1 obtained under the present embodiment
1hNMR,
13cNMR chemical displacement value is with embodiment 1.
2. the synthesis of compound 2
42g (146.7mmol) compound 1, acetonitrile 200ml is dropped in 500ml reaction flask, at room temperature (10 ~ 20 DEG C) add I-hydroxybenzotriazole 78g (176mmol), at room temperature (10 ~ 20 DEG C) stirring reaction 2h.System is cooled to about 0 DEG C, control temperature drips the acetonitrile solution 150ml of the O-Phenylene Diamine (63.5g, 586.8mmol) prepared at about 0 DEG C, drips and finishes, and about 0 DEG C is stirred 30min.Control temperature adds 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride 33.7g (176mmol) at about 0 DEG C, adds, 0 ~ 20 DEG C of reaction 8h.After reaction terminates, reaction solution is poured in 2500ml purified water, at room temperature (10 ~ 20 DEG C) making beating 12h.Filter, filter cake 800ml purified water is washed at twice, and after draining, wet product 40 ~ 50 DEG C of vacuum-drying 20h, obtain faint yellow solid compound 2,50.2g, yield 91%.
3. grace is for the synthesis of Nuo Te
In 1L reaction flask, add 40g compound 2, purified water 600ml, stir evenly and system is cooled to 0 ~ 10 DEG C simultaneously, temperature control 0 ~ 10 DEG C drips 10% hydrochloric acid, is dissolved to clearly for standard with system, stirs half an hour.Temperature control 0 ~ 10 DEG C drips 10% sodium hydroxide solution, regulates pH=8, and after adjustment, 0 ~ 10 DEG C is stirred 2h.Filter, filter cake purifies moisture three times washing with 600ml, and after draining, wet product 40 ~ 50 DEG C of vacuum-drying 20h, obtain off-white color solid grace for Nuo Te, 24.5g, yield 61.2%.Grace obtained under the present embodiment is for Nuo Te
1hNMR,
13cNMR chemical displacement value is with embodiment 1.
Claims (7)
1. PTS grace is for the synthetic method of Nuo Te, and it is characterized in that, the method comprises the steps:
1. with pyridine-3-methyl alcohol for starting raw material, first extend reagent to carry out carbochain and extend with carbochain and react, after carbochain extends, under catalyst action, carry out amidate action with Aminomethylbenzoic Acid and obtain compound 1, then crystallization is carried out, the consumption mol ratio that described starting raw material and carbochain extend reagent is 1:(1 ~ 2), the consumption mol ratio of starting raw material and Aminomethylbenzoic Acid is 1:(1 ~ 2), the consumption mol ratio of starting raw material and catalyzer is 1:(1 ~ 2), the pH value that during crystallization reaction, system controls is 4 ~ 5, and temperature of reaction-10 DEG C is to 60 DEG C;
2. there is amidate action and obtain compound 2 in compound 1 and O-Phenylene Diamine under catalyst action, namely grace is for the extraordinarily thick product of promise, described compound 1 is 1:(3 ~ 6 with the consumption mol ratio of O-Phenylene Diamine), compound 1 is 1:(1 ~ 4 with the consumption mol ratio of catalyzer), temperature of reaction-10 DEG C is to 60 DEG C;
3. compound 2 is analysed through acid-soluble alkali, and the refining grace that obtains is for the special fine work of promise, and controlling system pH when compound 2 dissolves is 2 ~ 3, and the pH value that during crystallization reaction, system controls is 8, and temperature of reaction is-10 DEG C to 60 DEG C:
Synthetic route is as follows:
2. preparation method according to claim 1, is characterized in that, step 1. in, in carbochain reaction of propagation, reaction reagent is N, N
,-carbonyl dimidazoles (CDI); Temperature of reaction is-10 DEG C to 40 DEG C; Solvent is tetrahydrofuran (THF), dimethyl formamide, dimethyl sulfoxide (DMSO), one or more mixture of acetonitrile.
3. preparation method according to claim 1, it is characterized in that, step 1. in, the catalyzer of carbochain reaction of propagation is N, N-diisopropylethylamine, triethylamine, pyridine, O-benzotriazole-N, one or more mixture in N, N', N'-tetramethyl-urea Tetrafluoroboric acid (TBTU), DMAP (DMAP), N-methylmorpholine.
4. preparation method according to claim 1, it is characterized in that, step 2. in, catalytic reagent is N, N'-carbonyl dimidazoles (CDI), 2-(7-azo benzotriazole)-N, N, one or more mixture in N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-1-base-oxygen base tripyrrole Wan Ji Phosphonium phosphofluoric acid (PyBOP), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), I-hydroxybenzotriazole (HOBT), methylsulfonic acid; Temperature of reaction is-10 DEG C to 40 DEG C; Solvent is tetrahydrofuran (THF), dimethyl formamide, dimethyl sulfoxide (DMSO), one or more mixture of acetonitrile.
5. preparation method according to claim 1, is characterized in that, step 3. in, grace is 1:(5-15 for the mass volume ratio (gram: milliliter) of the extraordinarily thick product of promise and water), temperature of reaction is-10 DEG C to 30 DEG C.
6. preparation method according to claim 3, it is characterized in that, step 1. in, used catalyst is N, N-diisopropylethylamine, triethylamine, DMAP (DMAP), N-methylmorpholine, solvent is dimethyl formamide or tetrahydrofuran (THF).
7. preparation method according to claim 4, it is characterized in that, step 2. in, used catalyst is N, N'-carbonyl dimidazoles (CDI), benzotriazole-1-base-oxygen base tripyrrole Wan Ji Phosphonium phosphofluoric acid (PyBOP), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), I-hydroxybenzotriazole (HOBT), methylsulfonic acid, solvent is dimethyl formamide or acetonitrile.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104876857A (en) * | 2015-05-12 | 2015-09-02 | 亿腾药业（泰州）有限公司 | Preparation of benzamide histone deacetylase inhibitor with differentiation and anti-proliferation activity |
| WO2017216761A1 (en) * | 2016-06-17 | 2017-12-21 | Dr. Reddy's Laboratories Limited | Solid forms of entinostat |
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