CN100516039C - Method for mass preparation of formamide phenol compound - Google Patents
Method for mass preparation of formamide phenol compound Download PDFInfo
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- CN100516039C CN100516039C CNB2007101320577A CN200710132057A CN100516039C CN 100516039 C CN100516039 C CN 100516039C CN B2007101320577 A CNB2007101320577 A CN B2007101320577A CN 200710132057 A CN200710132057 A CN 200710132057A CN 100516039 C CN100516039 C CN 100516039C
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Abstract
A method of the large-scale preparation of the dimensional formyl phenol amine compound provides a method of the large-scale preparation of the dimensional formyl phenol amine compound; the method is simple, low in cost, high in collection rate, and simple in the post processing. In the method, the wholly inversed dimensional formic acid is used as the starting material to react with the chlorination agent to produce the acyl chloride; then the acyl chloride reacts with the organic alkali to form the salt; the acyl ammonium salt and the substituted amino phenol do the amidation reaction to produce the dimensional formyl phenol amine compound. The substituted amino phenol is the compound as shown in the formula (I), wherein R is H, NO<SUB>2</SUB>, CO<SUB>2</SUB>R<SUB>1</SUB>, OR<SUB>1</SUB>, NHCOR<SUB>1</SUB>, SO<SUB>2</SUB>R<SUB>1</SUB>; R<SUB>1</SUB> is the alkyl of C1 to C4. The chlorination agent is the dichloro sulfoxide, phosphorus trichloride, phosphorus oxychloride and so on; the organic alkali is the triethylamine, pyridine and the derivative, and so on. The molar ration between the used chlorination agent and the wholly inversed dimensional formic acid is 1.0 to 5.0; the molar ration between the used substituted amino phenol and the wholly inversed dimensional formic acid is 1.0 to 10.0.
Description
Technical field
The present invention relates to the method for mass preparation of formamide phenol compound, belong to the synthesis technical field of amides in the organic chemistry.
Background technology
Dimension formyl phenol amine (fenretinide) has another name called fenretinide, is the all-trans-retinoic acid derivative of synthetic, and it is to develop prevention and the treatment that is used for mammary cancer by Johnson Co. the earliest.Show that after deliberation dimension formyl phenol amine can also be induced the apoptosis of kinds of tumor cells such as neuroblastoma, malignant liver, prostate cancer, ovarian cancer, cervical cancer; And with respect to other retinoid medicine, dimension formyl phenol amine has the advantages that toxicity is little, untoward reaction is low, becomes one of best substitute of retinoid medicine gradually.Except anti-tumor aspect performance curative effect, Italian Sirion company also uses it for ophthalmic diseases as the macula lutea degenerative change relevant with the age, recessiveness (heredity) macular dystrophy etc., is in the phase ii clinical trial at present.
The preparation method of the dimension formyl phenol amine of bibliographical information mainly contains following three kinds:
Method one (Chem.Pharm.Bull.2004,52 (5): 501-506) synthetic route is as follows:
This method is a raw material with all-trans-retinoic acid (ATRA) and p-aminophenol (4-AP), by condensing agent EDCI, directly obtains target product dimension formyl phenol amine.The characteristics of this method are that route is short, only need single step reaction, but need column chromatography just can obtain target product, and yield is not high, has only 48%, and used condensing agent EDCI is also relatively more expensive, therefore this method only is applicable in a small amount synthetic (less than 10mmol), is not suitable for scale operation.
Method two (Bulletin of the Korean Chemical Society.2002,23 (12): 806-1810) synthetic route is as follows:
This method is starting raw material with the all-trans-retinoic acid, form acyl chlorides with thionyl chloride, obtain target product with the p-aminophenol reaction again, this method also exists the shortcoming same with method one, promptly need just can obtain target product by column chromatography, and yield very low (20-25%) during mass production, so this method also only is applicable in a small amount synthetic (less than 10mmol), is not suitable for scale operation.
Method three (US5399757) synthetic route is as follows:
This method is starting raw material with the all-trans-retinoic acid; make acyl chlorides with the chlorination reagent Dimethylchloro-formamidinium Chloride reaction of gentleness, the hydroxyl of p-aminophenol and amino with obtaining target product with acyl chloride reaction again after the trimethyl silane protection.The characteristics of this method are just can obtain pure target product by recrystallization, and yield is higher, can scale operation; But synthetic route has increased the process of protection and deprotection, makes route become loaded down with trivial details, and upward the reaction of protecting group is a pyroreaction, and conversion unit is had relatively high expectations, and has increased cost.
Summary of the invention
Technical problem: the objective of the invention is deficiency at existing method, provide one simple, cheap, yield is high, aftertreatment is simple and be suitable for the method for preparing formamide phenol compound of scale operation.
Technical scheme: purpose of the present invention can reach by following measure:
The method of mass preparation of formamide phenol compound; be starting raw material with the all-trans-retinoic acid earlier, generate acyl chlorides with chlorination reaction, again with the organic bases salify; with the acyl group ammonium salt and the substituted-amino phenol generation amidate action that obtain, make formamide phenol compound then.
Wherein said substituted-amino phenol is formula (I) compound,
R is H, NO
2, CO
2R
1, OR
1, NHCOR
1, SO
2R
1, R
1Alkyl for C1～4.
Wherein the consumption mol ratio of chlorizating agent and all-trans-retinoic acid is that the consumption mol ratio of 1.0-5.0, substituted-amino phenol and all-trans-retinoic acid is 1.0-10.0; The temperature of all-trans-retinoic acid and chlorination reaction is-10～80 ℃, and the reaction times is 15min-8h; Acyl chlorides and organic bases temperature of reaction are-10～80 ℃, reaction times 10min-5h; Acyl group ammonium salt and substituted-amino phenol reactant temperature are-10～20 °; Chlorizating agent is thionyl chloride, phosphorus trichloride, phosphorus oxychloride etc.; Organic bases is triethylamine, pyridine and derivative thereof etc.; Reaction available solvent has N, dinethylformamide, toluene, benzene, methylene dichloride etc.
The first step of the present invention is starting raw material with the all-trans-retinoic acid, forms acyl chlorides with chlorizating agent, with the organic bases reaction, forms the acyl group ammonium salt again, has both improved the acidylate ability, has strengthened stability, has also improved the selectivity to amino.
Amino-phenol and the reaction of the first step product that second step of the present invention replaces difference, ice-water bath control reaction temperature are below 20 ℃, and the second step reaction product only needs recrystallization promptly to obtain pure target product.
This synthetic route of reacting described formamide phenol compound is as follows:
Wherein R is H, NO
2, CO
2R
1, OR
1, NHCOR
1, SO
2R
1, R
1Alkyl for C1～4.
Beneficial effect: characteristics of the present invention are that reactions steps is short, and the reaction conditions gentleness, is easy to get at the reaction reagent cheapness, good reaction selectivity does not have side reaction, only needs recrystallization just can obtain the pure product (purity is more than 98%) of target product, yield height (more than 80%) can scale operation.
Embodiment
Embodiment one
In 1 liter eggplant-shape bottle, add 47.3ml thionyl chloride (SOCl
2, 0.666mol) with the anhydrous N of 51.3ml, and dinethylformamide (DMF, 0.666mol), at the following stirring of nitrogen protection 1h.Add the 500ml dry DMF contain 100g all-trans-retinoic acid (0.333mol) again, under lucifuge, 0 ℃ condition, react 3h, obtain red solution of acid chloride.And then adding 92.3ml triethylamine (Et
3N 0.666mol), continues reaction 1h, obtains scarlet acyl group ammonium salt solution.
In 2 liters of three-necked bottles that thermometer, dropping funnel and drying tube be housed, add 108.0g p-aminophenol (0.99mol), dissolve with the 500ml dry DMF, drip above-mentioned solution of acid chloride then, temperature is controlled at below 20 ℃ in the dropping process, continue to be stirred to after dropwising thin-layer chromatography (TLC) monitoring reaction fully till.Pour reaction solution into 5 liters of NH
4In the Cl saturated aqueous solution, ethyl acetate extraction, organic layer washes with water successively then, saturated common salt is washed, Na
2SO
4Dried overnight is filtered, is concentrated, and obtains the deep yellow crude product, uses ethyl alcohol recrystallization again, obtains the 105.2.g yellow solid, yield 80.7%, mp.:170-172 ℃.
MS：[M+H]
+＝392.3；
1HNMR(CDCl
3)δ：1.04(s，6H)，1.46-1.50(m，2H)，1.58-1.65(m，2H)，1.73(s，3H)，2.01-2.05(m，5H)，5.08(brs，1H)，5.79(s，1H)，6.12-6.31(m，4H)，6.78-6.80(d，J＝8.8，2H)，6.94-7.02(dd，J1＝11.5，J2＝11.4，1H)，7.0926(brs，1H)，7.37-7.40(d，J＝8.9，2H，)
Embodiment two
In 1 liter eggplant-shape bottle, add 61.2ml phosphorus oxychloride (POCl
3, 0.666mol) with 51.3ml DMF (0.666mol), at the following stirring of nitrogen protection 1h.Add the 500ml dry DMF contain 100g all-trans-retinoic acid (0.333mol) again, under lucifuge, 0 ℃ condition, react 3h, obtain red solution of acid chloride.And then adding 92.3ml Et
3N (, 0.666mol), continue reaction 1h, obtain scarlet acyl group ammonium salt solution.
In 2 liters of three-necked bottles that thermometer, dropping funnel and drying tube be housed, add 108.0g p-aminophenol (0.99mol), dissolve with the 500ml dry DMF, drip above-mentioned solution of acid chloride then, temperature is controlled at below 20 ℃ in the dropping process, continue to be stirred to after dropwising the TLC monitoring reaction fully till.Pour reaction solution into 5 liters of NH
4In the Cl saturated aqueous solution, ethyl acetate extraction, organic layer washes with water successively then, saturated common salt is washed, Na
2SO
4Dried overnight is filtered, is concentrated, and obtains the deep yellow crude product, uses ethyl alcohol recrystallization again, obtains the 75.1g yellow solid, yield 57.6%,
Embodiment three
In 1 liter eggplant-shape bottle, add 47.3mlSOCl
2(0.666mol) with 51.3ml DMF (0.666mol), at the following stirring of nitrogen protection 1h.Add the 500ml dry DMF contain 100g all-trans-retinoic acid (0.333mol) again, under lucifuge, 0 ℃ condition, react 3h, obtain red solution of acid chloride.And then (Py 0.666mol), continues reaction 1h, obtains scarlet acyl group ammonium salt solution to add the 53.8ml pyridine.
In 2 liters of three-necked bottles that thermometer, dropping funnel and drying tube be housed, add 108.0g p-aminophenol (0.99mol), dissolve with the 500ml dry DMF, drip above-mentioned solution of acid chloride then, temperature is controlled at below 20 ℃ in the dropping process, continue to be stirred to after dropwising the TLC monitoring reaction fully till.Pour reaction solution into 5 liters of NH
4In the Cl saturated aqueous solution, ethyl acetate extraction, organic layer washes with water successively then, saturated common salt is washed, Na
2SO
4Dried overnight is filtered, is concentrated, and obtains the deep yellow crude product, uses ethyl alcohol recrystallization again, obtains the 95.7.g yellow solid, yield 73.4%
Embodiment four
In 1 liter eggplant-shape bottle, add 47.3ml SOCl
2(0.666mol) with 51.3ml dry DMF (0.666mol), at the following stirring of nitrogen protection 1h.Add the 500ml dry DMF contain 100g all-trans-retinoic acid (0.333mol) again, under lucifuge, 0 ℃ condition, react 3h, obtain red solution of acid chloride.And then adding 92.3ml Et
3N (0.666mol) continues reaction 1h, obtains scarlet acyl group ammonium salt solution.
In 2 liters of three-necked bottles that thermometer, dropping funnel and drying tube be housed, add 152.5g 2-nitro-4-amino-phenol (0.99mol), dissolve with the 500ml dry DMF, drip above-mentioned solution of acid chloride then, temperature is controlled at below 20 ℃ in the dropping process, continue to be stirred to after dropwising the TLC monitoring reaction fully till.Pour reaction solution into 5 liters of NH
4In the Cl saturated aqueous solution, ethyl acetate extraction, organic layer washes with water successively then, saturated common salt is washed, Na
2SO
4Dried overnight is filtered, is concentrated, and obtains the deep yellow crude product, uses ethyl alcohol recrystallization again, obtains the 110.3g yellow solid, yield 75.9%, mp.:159-160 ℃.
MS：[M+H]
+＝437.3。
Embodiment five
In 1 liter eggplant-shape bottle, add 47.3ml SOCl
2(0.666mol) with 51.3ml dry DMF (0.666mol), at the following stirring of nitrogen protection 1h.Add the 500ml dry DMF contain 100g all-trans-retinoic acid (0.333mol) again, under lucifuge, 0 ℃ condition, react 3h, obtain red solution of acid chloride.And then adding 92.3ml Et
3N (0.666mol) continues reaction 1h, obtains scarlet acyl group ammonium salt solution.
In 2 liters of three-necked bottles that thermometer, dropping funnel and drying tube be housed, add 137.6g 2-methoxyl group-5-amino-phenol (0.99mol), dissolve with the 500ml dry DMF, drip above-mentioned solution of acid chloride then, temperature is controlled at below 15 ℃ in the dropping process, continue to be stirred to after dropwising the TLC monitoring reaction fully till.Pour reaction solution into 5 liters of NH
4In the Cl saturated aqueous solution, ethyl acetate extraction, organic layer washes with water successively then, saturated common salt is washed, Na
2SO
4Dried overnight is filtered, is concentrated, and obtains the deep yellow crude product, uses ethyl alcohol recrystallization again, obtains the 101.8g yellow solid, yield 72.54%, mp.:118-120 ℃.
MS：[M+H]
+＝422.1。
Embodiment six
In 1 liter eggplant-shape bottle, add 47.3ml SOCl
2(0.666mol) with 51.3ml dry DMF (0.666mol), at the following stirring of nitrogen protection 1h.Add the 500ml dry DMF contain 100g all-trans-retinoic acid (0.333mol) again, under lucifuge, 0 ℃ condition, react 3h, obtain red solution of acid chloride.And then adding 92.3ml Et
3N (0.666mol) continues reaction 1h, obtains scarlet acyl group ammonium salt solution.
In 2 liters of three-necked bottles that thermometer, dropping funnel and drying tube be housed, add 165.5g 2-hydroxyl-4-Methyl anthranilate (0.99mol), dissolve with the 500ml dry DMF, drip above-mentioned solution of acid chloride then, temperature is controlled at below 20 ℃ in the dropping process, continue to be stirred to after dropwising the TLC monitoring reaction fully till.Pour reaction solution into 5 liters of NH
4In the Cl saturated aqueous solution, ethyl acetate extraction, organic layer washes with water successively then, saturated common salt is washed, Na
2SO
4Dried overnight is filtered, is concentrated, and obtains the deep yellow crude product, uses ethyl alcohol recrystallization again, obtains the 105.7g yellow solid, yield 70.6%, mp.:167-169 ℃.
MS：[M+H]
+＝450.5。
Embodiment seven
In 1 liter eggplant-shape bottle, add 47.3ml SOCl
2(0.666mol) with 51.3ml dry DMF (0.666mol), at the following stirring of nitrogen protection 1h.Add the 500ml dry DMF contain 100g all-trans-retinoic acid (0.333mol) again, under lucifuge, 0 ℃ condition, react 3h, obtain red solution of acid chloride.And then adding 93.3ml Et
3N (0.666mol) continues reaction 1h, obtains scarlet acyl group ammonium salt solution.
In 2 liters of three-necked bottles that thermometer, dropping funnel and drying tube be housed, add 178.2g N-(2-hydroxyl-4-aminophenyl) propionic acid amide (0.99mol), dissolve with the 500ml dry DMF, drip above-mentioned solution of acid chloride then, temperature is controlled at below 20 ℃ in the dropping process, continue to be stirred to after dropwising the TLC monitoring reaction fully till.Pour reaction solution into 5 liters of NH
4In the Cl saturated aqueous solution, ethyl acetate extraction, organic layer washes with water successively then, saturated common salt is washed, Na
2SO
4Dried overnight is filtered, is concentrated, and obtains the deep yellow crude product, uses ethyl alcohol recrystallization again, obtains the 117.3g yellow solid, yield 76.2%, mp.:188-190 ℃.
MS：[M+H]
+＝463.5。
Embodiment eight
In 1 liter eggplant-shape bottle, add 47.3ml SOCl
2(0.666mol) with 51.3ml dry DMF (0.666mol), at the following stirring of nitrogen protection 1h.Add the 500ml dry DMF contain 100g all-trans-retinoic acid (0.333mol) again, under lucifuge, 0 ℃ condition, react 3h, obtain red solution of acid chloride.And then adding 92.3ml Et
3N (0.666mol) continues reaction 1h, obtains scarlet acyl group ammonium salt solution.
In 2 liters of three-necked bottles that thermometer, dropping funnel and drying tube be housed, add 199.0g 3-hydroxyl-4-amino phenyl sulfonyl acetoacetic ester (0.99mol), dissolve with the 500ml dry DMF, drip above-mentioned solution of acid chloride then, temperature is controlled at below 20 ℃ in the dropping process, continue to be stirred to after dropwising the TLC monitoring reaction fully till.Pour reaction solution into 5 liters of NH
4In the Cl saturated aqueous solution, ethyl acetate extraction, organic layer washes with water successively then, saturated common salt is washed, Na
2SO
4Dried overnight is filtered, is concentrated, and obtains the deep yellow crude product, uses ethyl alcohol recrystallization again, obtains the 118.5g yellow solid, yield 73.6%, mp.:145-147 ℃.
MS：[M+H]
+484.1。
Claims (1)
1, a kind of method of mass preparation of formamide phenol compound, it is characterized in that being starting raw material with the all-trans-retinoic acid earlier, generate acyl chlorides with chlorination reaction, again with the organic bases salify, with the acyl group ammonium salt and the substituted-amino phenol generation amidate action that obtain, make formamide phenol compound then; Described chlorizating agent is thionyl chloride, phosphorus trichloride, phosphorus oxychloride; Organic bases is triethylamine, pyridine; The consumption mol ratio of chlorizating agent and all-trans-retinoic acid is 1.0-5.0, and the consumption mol ratio of substituted-amino phenol and all-trans-retinoic acid is 1.0-10.0; The temperature of all-trans-retinoic acid and chlorination reaction is-10～80 ℃, and the reaction times is 15min-8h; Acyl chlorides and organic bases temperature of reaction are-10～80 ℃, and the reaction times is 10min-5h; Acyl group ammonium salt and substituted-amino phenol reactant temperature are-10～20 ℃; Described substituted-amino phenol is formula (I) compound,
Wherein R is H, NO
2, CO
2R
1, OR
1, NHCOR
1Or SO
2R
1, R
1Alkyl for C1～4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007101320577A CN100516039C (en) | 2007-09-11 | 2007-09-11 | Method for mass preparation of formamide phenol compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007101320577A CN100516039C (en) | 2007-09-11 | 2007-09-11 | Method for mass preparation of formamide phenol compound |
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| CN101139311A CN101139311A (en) | 2008-03-12 |
| CN100516039C true CN100516039C (en) | 2009-07-22 |
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|---|---|---|---|
| CNB2007101320577A Expired - Fee Related CN100516039C (en) | 2007-09-11 | 2007-09-11 | Method for mass preparation of formamide phenol compound |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101623277B (en) * | 2008-07-08 | 2014-07-16 | 上海交通大学医学院附属瑞金医院 | Suwei A amine, novel application of active derivative and medicine composition thereof |
| CN106977563B (en) * | 2017-04-12 | 2019-11-08 | 梯尔希（南京）药物研发有限公司 | A kind of synthetic method of deuterium-labeled glucosiduronate retinamide |
| CN114436924B (en) * | 2022-02-21 | 2023-09-29 | 青岛三人行化学有限公司 | Synthesis method of hydroxy pinacolone retinoic acid ester |
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2007
- 2007-09-11 CN CNB2007101320577A patent/CN100516039C/en not_active Expired - Fee Related
Non-Patent Citations (4)
| Title |
|---|
| Synthesis and Biological Activity of Novel RetinamideandRetinoate. Soo-Jong Um et al.Chem. Pharm. Bull.,Vol.52 No.5. 2004 |
| Synthesis and Biological Activity of Novel RetinamideandRetinoate. Soo-Jong Um et al.Chem. Pharm. Bull.,Vol.52 No.5. 2004 * |
| Synthesis and Preliminary Biological Studies ofNovelRetinamide Derivatives. Hong S. Sin et al.Bull. Korean Chem. Soc.,Vol.23 No.12. 2002 |
| Synthesis and Preliminary Biological Studies ofNovelRetinamide Derivatives. Hong S. Sin et al.Bull. Korean Chem. Soc.,Vol.23 No.12. 2002 * |
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Assignee: Suzhou Dongnan Pharmaceutical Research & Development Co., Ltd. Assignor: Southeast University Contract fulfillment period: 2009.12.12 to 2027.9.10 contract change Contract record no.: 2010320000025 Denomination of invention: Method for mass preparation of formamide phenol compound Granted publication date: 20090722 License type: Exclusive license Record date: 2010.1.26 |
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