CN103497175B - Prepare the method for Revlimid - Google Patents

Prepare the method for Revlimid Download PDF

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CN103497175B
CN103497175B CN201310472457.8A CN201310472457A CN103497175B CN 103497175 B CN103497175 B CN 103497175B CN 201310472457 A CN201310472457 A CN 201310472457A CN 103497175 B CN103497175 B CN 103497175B
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CN103497175A (en
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许勇
李莉娥
郭涤亮
乐洋
张绪文
杨仲文
王磊
田华
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湖北生物医药产业技术研究院有限公司
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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of products other than chlorine, adipic acid, caprolactam, or chlorodifluoromethane, e.g. bulk or fine chemicals or pharmaceuticals
    • Y02P20/55Synthetic design, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses the method preparing Revlimid.Present method with 3-amino-2-methyl phenylformic acid for starting raw material synthesizes Revlimid.Utilize the method preparing Revlimid of the present invention effectively can prepare Revlimid, and technique is simple, combined coefficient is high, and the purity of prepared Revlimid is higher.In addition, this preparation method also has that starting raw material is easy to get, technological operation is simple, reaction conditions is gentle, without the need to special reaction equipment, in preparation process, be not difficult to the advantages such as the compound that is separated, thus is more suitable for extensive, suitability for industrialized production Revlimid.

Description

Prepare the method for Revlimid

Technical field

The present invention relates to medical art.In particular to the method preparing Revlimid.

Background technology

Revlimid (Lenalidomide/Revlimid, compound 1), chemistry 3-(7-amino-3-oxo-1H-isoindole-2-base) piperidines-2,6-diketone by name, its chemical structure is as follows:

Revlimid is a kind of immunomodulator having angiogenesis inhibitor, immunomodulatory and directly kill the multiple actions such as tumour cell, it is developed by Celgene company of the U.S. and obtains U.S. FDA in December, 2005 and ratifies, be used for the treatment of multiple myeloma and myelodysplastic syndrome, be used for the treatment of the reinforcement version that morning sickness once caused thousands of baby due defect Thalidomides (thalidomide), there are anticancer potentiality, compared with Thalidomide, its less adverse effect, research proves that it can not cause baby due defect.Although the method preparing Revlimid is at present a lot, there is complicated process of preparation, combined coefficient is low, production cost is high, production security is low, pollute physical environment, be difficult to the shortcomings such as suitability for industrialized production.

Therefore, the method preparing Revlimid at present still haves much room for improvement.

Summary of the invention

The present invention is intended at least to solve one of technical problem existed in prior art.For this reason, the present invention proposes the method effectively can preparing Revlimid.

The present invention proposes a kind of method preparing Revlimid.According to embodiments of the invention, the method comprises:

1) with reference to following formula, the esterification of compound generation shown in formula 2 is made, to obtain compound shown in formula 3,

2) with reference to following formula, compound shown in described formula 3 is contacted with amino protecting agent, to obtain compound shown in formula 4,

3) with reference to following formula, compound generation halogenating reaction shown in described formula 4 is made, to obtain compound shown in formula 5,

4) with reference to following formula, compound shown in compound with formula 6 shown in described formula 5 is contacted, to obtain compound shown in formula 7,

and

5) with reference to following formula, by compound generation deprotection reaction shown in described formula 7, to obtain compound shown in described formula 1,

Term " contact " used in this article should be interpreted broadly, and it can be any mode that can make at least two kinds of reactant generation chemical reactions, such as, can be mixed under suitable condition by two kinds of reactants.In this article, " compound N ", in this article sometimes also referred to as " shown in formula N compound ", N is the arbitrary integer of 1-13 in this article, and such as " compound 2 " also can be called " shown in formula 2 compound " in this article.

The similar description such as term " first ", " second " used in this article only for describing object, and can not be interpreted as instruction or hint relative importance or imply the quantity indicating indicated technical characteristic.Thus, be limited with " first ", the feature of " second " can express or impliedly comprise one or more these features.In describing the invention, except as otherwise noted, the implication of " multiple " is two or more, unless otherwise clear and definite restriction.

Utilize and effectively can prepare Revlimid according to the method preparing Revlimid of the embodiment of the present invention, and preparation technology is simple, combined coefficient is high, and the purity of prepared Revlimid is higher, and this preparation method has no bibliographical information.In addition, this preparation method also has that starting raw material is easy to get, reaction conditions is gentle, without the need to special reaction equipment, in preparation process, be not difficult to the advantages such as the compound that is separated, thus is more suitable for extensive, suitability for industrialized production Revlimid.

In addition, following additional technical characteristic can also be had according to the method preparing Revlimid of the embodiment of the present invention:

According to embodiments of the invention, R1 to be carbon atom number be 1 ~ 10 alkyl, preferred R1 is methyl, and R2 is Br or Cl, and preferred R2 is Br.

According to embodiments of the invention, make the means of the esterification of compound generation shown in formula 2, and be not particularly limited.Such as according to some embodiments of the present invention, in step 1), when there is acid catalyst, compound shown in described formula 2 being contacted with monohydroxy-alcohol, there is described esterification, thus obtains compound shown in described formula 3.According to other embodiment of the present invention, at the temperature of 50 ~ 80 degrees Celsius, carry out described esterification 8 ~ 15 hours.

According to embodiments of the invention, kind and the usage quantity thereof of described acid catalyst and monohydroxy-alcohol are not particularly limited.Such as according to some embodiments of the present invention, described acid catalyst is at least one being selected from tosic acid and sulfuric acid, described monohydroxy-alcohol to be carbon atom number be 1 ~ 10 monohydroxy-alcohol, particular methanol.According to other embodiment of the present invention, shown in shown formula 2, the mol ratio of compound and described acid catalyst is 1:1.2 ~ 3.0.

According to embodiments of the invention, by the means that compound shown in described formula 3 contacts with amino protecting agent, and be not particularly limited.Such as according to some embodiments of the present invention; described amino protecting agent is be selected from least one in tert-Butyl dicarbonate, chloroformic acid benzyl ester, bromobenzyl and Tosyl chloride; preferred described amido protecting agent is be selected from least one in tert-Butyl dicarbonate and chloroformic acid benzyl ester, and most preferably described amido protecting agent is tert-Butyl dicarbonate.

According to some embodiments of the present invention; in step 2) in; in the first organic solvent; when there is alkaline catalysts, compound shown in described formula 3 is contacted with described amino protecting agent, to carry out amido protecting reaction; thus obtain compound shown in formula 4; wherein, described first organic solvent is at least one being selected from halogenated hydrocarbon organic solvent and ether organic solvent, and described alkaline catalysts is at least one being selected from organic bases and mineral alkali.

According to some embodiments of the present invention, described halogenated hydrocarbon organic solvent is for being selected from methyl chloride, methylene dichloride, trichloromethane, monochloroethane, the at least one of ethylene dichloride and trichloroethane, preferred described halogenated hydrocarbon organic solvent is at least one being selected from methylene dichloride and trichloromethane, described ether organic solvent is for being selected from methyl ether, ether, sherwood oil, isopropyl ether, methyl tertiary butyl ether, ethyl-butyl ether, Ethyl Tertisry Butyl Ether, tetrahydrofuran (THF), tetrahydropyrans, the at least one of dioxane and methyl-phenoxide, preferred described ether organic solvent is for being selected from sherwood oil, tetrahydrofuran (THF), the at least one of methyl tertiary butyl ether and dioxane, described alkaline catalysts is at least one being selected from DMAP and triethylamine.

According to some embodiments of the present invention; shown in described formula 3, the mol ratio of compound and described amido protecting agent is 1:1.1 ~ 2.0; shown in described formula 3, the mol ratio of compound and alkaline catalysts is 1:1.5 ~ 3.0, and described amido protecting reaction carries out 3 ~ 8 hours at the temperature of 0 ~ 45 degree Celsius.

According to embodiments of the invention, make the means of compound generation halogenating reaction shown in described formula 4, and be not particularly limited.Such as according to some embodiments of the present invention, in step 3), in a second organic solvent, when there is initiator, by compound and halogenating agent shown in described formula 4, to carry out halogenating reaction, thus generate compound shown in described formula 5, wherein, described second organic solvent is for being selected from methyl chloride, methylene dichloride, trichloromethane, monochloroethane, the at least one of ethylene dichloride and trichloroethane, be preferably at least one be selected from methylene dichloride and trichloromethane, described halogenating agent is for being selected from cupric bromide, hydrogen bromide, N-bromo-succinimide (NBS), bromination dimethyl bromo sulphur (DMBS), Sodium Bromide, Potassium Bromide, at least one in brometo de amonio and bromine chloride, preferred described bromizating agent is N-bromo-succinimide, described initiator is for being selected from Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile), the at least one of benzoyl peroxide and di-isopropyl peroxydicarbonate, preferred described initiator is Diisopropyl azodicarboxylate.

According to some embodiments of the present invention, shown in described formula 4, the mol ratio of compound and described bromizating agent is 1:1.05 ~ 2.0, shown in described formula 4, the mol ratio of compound and described initiator is 1:0.1 ~ 0.5, and described halogenating reaction carries out 3 ~ 8 hours at the temperature of 30 ~ 80 degrees Celsius.

According to embodiments of the invention, by the means that compound shown in compound with formula 6 shown in described formula 5 contacts, and be not particularly limited.Such as according to some embodiments of the present invention, in step 4), in the 3rd organic solvent, when there is basic cpd, compound shown in compound with formula 6 shown in formula 5 is contacted, there is ring-closure reaction, thus compound shown in production 7, wherein, described 3rd organic solvent is for being selected from N, dinethylformamide (DMF) and N, at least one in N-N,N-DIMETHYLACETAMIDE, preferred N, dinethylformamide, described basic cpd is at least one being selected from organic bases and mineral alkali, preferred described basic cpd is at least one being selected from salt of wormwood and triethylamine.

According to some embodiments of the present invention, in step 4), shown in described formula 5, shown in compound and described formula 6, the mol ratio of compound is 1:1.0 ~ 1.5, shown in described formula 5, the mol ratio of compound and described basic cpd is 1:1.5 ~ 3.5, and described ring-closure reaction carries out 8 ~ 16 hours at the temperature of 50 ~ 100 degrees Celsius.

According to embodiments of the invention, by the means of compound generation deprotection reaction shown in described formula 7, and be not particularly limited.Such as according to some embodiments of the present invention, in step 5), in the 3rd organic solvent, when there is acid, make compound generation deprotection reaction shown in described formula 7, so that compound shown in production 1, wherein, described 3rd organic solvent is methyl chloride, methylene dichloride, trichloromethane, monochloroethane, ethylene dichloride and trichloroethane, methyl ether, ether, sherwood oil, isopropyl ether, methyl tertiary butyl ether, ethyl-butyl ether, Ethyl Tertisry Butyl Ether, tetrahydrofuran (THF), tetrahydropyrans, the at least one of dioxane and methyl-phenoxide, preferably described 3rd organic solvent is for being selected from methylene dichloride and trichloromethane, sherwood oil, tetrahydrofuran (THF), at least one in methyl tertiary butyl ether and dioxane, described acid is for being selected from least one in organic acid and mineral acid, preferred described acid is for being selected from trifluoracetic acid, hydrochloric acid, the at least one of trifluoromethanesulfonic acid and p-methyl benzenesulfonic acid.

According to some embodiments of the present invention, shown in described formula 7, the mol ratio of compound and described acid is 1:0.5 ~ 2.5, and described deprotection reaction carries out 5 ~ 10 hours under 0 ~ 35 degree Celsius.

According to embodiments of the invention, in step 5), in the 4th organic solvent, when there is palladium and ammonium formiate, make compound generation deprotection reaction shown in described formula 7, so that compound shown in production 1, wherein, described 4th organic solvent is for being selected from methyl alcohol, ethanol, propyl alcohol, butanols and ethylene glycol, methyl ether, ether, sherwood oil, isopropyl ether, methyl tertiary butyl ether, ethyl-butyl ether, Ethyl Tertisry Butyl Ether, tetrahydrofuran (THF), tetrahydropyrans, the at least one of dioxane and methyl-phenoxide, preferably described 4th organic solvent is for being selected from methyl alcohol, sherwood oil, tetrahydrofuran (THF), at least one in methyl tertiary butyl ether and dioxane.Again according to some embodiments of the present invention, described palladium provides with palladium charcoal form, and described deprotection reaction carries out 2 ~ 6 hours at the temperature of 20 ~ 60 degrees Celsius.

According to embodiments of the invention, described deprotection reaction carries out in an inert atmosphere, use the kind of rare gas element to be not particularly limited, preferred described inert atmosphere is made up of at least one be selected from nitrogen and argon gas.

Following advantages can be realized one of at least according to the method preparing Revlimid of the embodiment of the present invention:

1) according to the method preparing Revlimid of the embodiment of the present invention, the route of this synthesis Revlimid has no bibliographical information, and combined coefficient is high, and the purity of prepared Revlimid is also higher;

2) according to the method preparing Revlimid of the embodiment of the present invention, reaction conditions is gentle, without the need to the equipment of special reaction, also without the need to using danger, severe toxicity and special reagent;

3) according to the method preparing Revlimid of the embodiment of the present invention, the compound be separated is not difficult in preparation process, gained intermediate and finished product can be obtained by recrystallization, and some intermediate can not need separation and purification, and whole process does not need the complicated separation and purification such as column chromatography to operate yet;

4) according to the method preparing Revlimid of the embodiment of the present invention, starting raw material used and reagent are easily buied from market, thus are conducive to reducing production cost;

5) prepare the method for Revlimid according to an embodiment of the invention, technological operation is simple, and with short production cycle, production security is high, thus is more suitable for extensive, suitability for industrialized production Revlimid.

Additional aspect of the present invention and advantage will part provide in the following description, and part will become obvious from the following description, or be recognized by practice of the present invention.

Embodiment

Be described below in detail embodiments of the invention, it should be noted that embodiment described below is exemplary, only for explaining the present invention, and can not limitation of the present invention be interpreted as.In addition, if do not clearly not stated, adopted in the following embodiments all reagent are, and market can be buied, or can according to herein or known method synthesis, for the reaction conditions do not listed, be also that those skilled in the art easily obtain.

General method

With reference to following formula, in the examples below that, the method preparing Revlimid method mainly comprises the following steps:

1) esterification: 3-amino-2-methyl phenylformic acid (compound 2), through acid, contacts with monohydroxy-alcohol and esterification occurs obtains 3-amino-2-methyl methyl benzoate (compound 3);

2) amido protecting reaction: compound 3 contacts with amino protecting agent, is obtained by reacting compound 4;

3) addition reaction: compound 4, through bromizating agent and initiator, halogenating reaction occurs and obtains compound 5;

4) ring-closure reaction: compound 5, through alkali, with 3-amino-2,6-dioxopiperidine hydrochlorides (compound 6), cyclization occurs and is obtained by reacting compound 7;

5) deprotection reaction: deprotection reaction occurs compound 7, finally obtains Revlimid (compound 1).

According to embodiments of the invention, above-mentionedly prepare Revlimid method, the synthetic route that can preferably adopt is as follows:

Embodiment 1: esterification

(100 grams, 3-amino-2-methyl phenylformic acid, 0.662 mole) and tosic acid (200 grams, 1.162 mole), add methyl alcohol 3000 milliliters, stir, back flow reaction 10 hours, ethyl acetate 3000 milliliters and 1M wet chemical 3000 milliliters stirring is added after being chilled to room temperature, filter, filtrate is extracted with ethyl acetate, with wet chemical and the saturated common salt water washing of 1M, after organic layer drying, concentrating under reduced pressure obtains 3-amino-2-methyl methyl benzoate (compound 3,93.0 grams, 0.564 mole), yield 85%. 1H NMR(CDCl 3):δ2.36(s,3H),3.82(s,3H),6.71-6.77(m,1H),6.99-7.01(m,1H),7.16-7.20(m,1H).MS(m/z):165[M+H] +

Embodiment 2: esterification

(100 grams, 3-amino-2-methyl phenylformic acid, 0.662 mole) and (63 milliliters, sulfuric acid, 1.162 mole), add methyl alcohol 3000 milliliters, stir, back flow reaction 10 hours, ethyl acetate 3000 milliliters and 1M wet chemical 3000 milliliters stirring is added after being chilled to room temperature, filter, filtrate is extracted with ethyl acetate, with wet chemical and the saturated common salt water washing of 1M, after organic layer drying, concentrating under reduced pressure obtains 3-amino-2-methyl methyl benzoate (compound 3,79.0 grams, 0.483 mole), yield 73%.MS(m/z):165[M+H] +

Embodiment 3: amido protecting reacts

By compound 3(93.0 gram, 0.564 mole) be dissolved in methylene dichloride 1000 milliliters, add tert-Butyl dicarbonate (147.5 grams, 0.677 mole), temperature control 25 degrees Celsius, stirring reaction is after 5 hours, and dichloromethane extraction, with saturated sodium bicarbonate aqueous solution and saturated common salt water washing, obtain 3-tert.-butoxy methane amide-2-methyl-toluate (compound 4 (a), 143.5 grams, 0.541 mole), yield 96%. 1H NMR(CDCl 3):δ1.41(s,9H),2.35(s,3H),3.87(s,3H),6.92-6.97(m,1H),7.05-7.11(m,1H),7.56-7.59(m,1H).MS(m/z):265[M+H] +

Embodiment 4: amido protecting reacts

By compound 3(93.0 gram, 0.564 mole) be dissolved in tetrahydrofuran (THF) 800 milliliters, add triethylamine (118 milliliters, 0.846 mole), temperature control 0 degree Celsius, drips chloroformic acid benzyl ester (another name CbzCl, 93 milliliters, 0.677 mole), after stirring at room temperature reacts 3 hours, dichloromethane extraction, with saturated sodium bicarbonate aqueous solution and saturated common salt water washing, obtain 3-benzyloxy-formyl amine-2-methyl-toluate (compound 4 (b), 146.7 grams, 0.491 mole), yield 87%. 1H NMR(CDCl 3):δ2.33(s,3H),3.86(s,3H),5.22(s,2H),6.94-7.00(m,1H),7.05-7.15(m,3H),7.18-7.22(m,3H),7.52-7.57(m,1H).MS(m/z):300[M+H] +

Embodiment 5: addition reaction

By 3-tert.-butoxy methane amide-2-methyl-toluate (compound 4 (a), 150 grams, 0.566 mole) be dissolved in trichloromethane 1200 milliliters, add N-bromo-succinimide (110 grams, 0.618 mole), Diisopropyl azodicarboxylate (16.4 grams, 0.100 mole), back flow reaction 6 hours, filters after being cooled to room temperature, filtrate chloroform extraction, with water, saturated common salt water washing, organic layer drying is concentrated, obtains 2-brooethyl-3-tert.-butoxy formamide benzene methyl-formiate (compound 5 (a), 142 grams, 0.414 mole), yield 73%.MS(m/z):345[M+H] +

Embodiment 6: addition reaction

By 3-tert.-butoxy methane amide-2-methyl-toluate (compound 4 (a), 150 grams, 0.566 mole) be dissolved in trichloromethane 1200 milliliters, add cupric bromide (138 grams, 0.618 mole), Diisopropyl azodicarboxylate (16.4 grams, 0.100 mole), back flow reaction 6 hours, filters after being cooled to room temperature, filtrate chloroform extraction, with water, saturated common salt water washing, organic layer drying is concentrated, obtains 2-brooethyl-3-tert.-butoxy formamide benzene methyl-formiate (compound 5 (a), 88 grams, 0.255 mole), yield 45%.MS(m/z):345[M+H] +

Embodiment 7: addition reaction

By 3-tert.-butoxy methane amide-2-methyl-toluate (compound 4 (a), 150 grams, 0.566 mole) be dissolved in trichloromethane 1200 milliliters, add N-bromo-succinimide (110 grams, 0.618 mole), benzoyl peroxide (24.2 grams, 0.100 mole), back flow reaction 6 hours, filters after being cooled to room temperature, filtrate chloroform extraction, with water, saturated common salt water washing, organic layer drying is concentrated, obtains 2-brooethyl-3-tert.-butoxy formamide benzene methyl-formiate (compound 5 (a), 101 grams, 0.294 mole), yield 52%.MS(m/z):345[M+H] +

Embodiment 8: addition reaction

By 3-tert.-butoxy methane amide-2-methyl-toluate (compound 4 (a), 150 grams, 0.566 mole) be dissolved in 1200 milliliters, tetracol phenixin, add N-bromo-succinimide (110 grams, 0.618 mole), Diisopropyl azodicarboxylate (16.4 grams, 0.100 mole), back flow reaction 6 hours, filters after being cooled to room temperature, filtrate chloroform extraction, with water, saturated common salt water washing, organic layer drying is concentrated, obtains 2-brooethyl-3-tert.-butoxy formamide benzene methyl-formiate (compound 5 (a), 150 grams, 0.436 mole), yield 77%.MS(m/z):345[M+H] +

Embodiment 9: addition reaction

By 3-benzyloxy-formyl amine-2-methyl-toluate (compound 4 (a), 150 grams, 0.500 mole) be dissolved in trichloromethane 1200 milliliters, add N-bromo-succinimide (97 grams, 0.546 mole), Diisopropyl azodicarboxylate (14.5 grams, 0.088 mole), back flow reaction 6 hours, filters after being cooled to room temperature, filtrate chloroform extraction, with water, saturated common salt water washing, organic layer drying is concentrated, obtains 2-brooethyl-3-benzyloxy-formyl amine methyl benzoate (compound 5 (b), 132 grams, 0.350 mole), yield 70%.MS(m/z):379[M+H] +

Embodiment 10: ring-closure reaction

By obtained 2-brooethyl-3-tert.-butoxy formamide benzene methyl-formiate (compound 5 (a), 142 grams, 0.414 mole) and 3-amino-2, 6-dioxopiperidine hydrochloride (compound 6, 75 grams, 0.455 mole) be dissolved in N, dinethylformamide 800 milliliters, add (170 grams, salt of wormwood, 1.242 mole), temperature control 60 degrees Celsius, stirring reaction 10 hours, be cooled to room temperature, pour in frozen water and stir 1 hour, filter, wash with water, dry, obtain 3-(7-tert.-butoxy formamido--3-oxo-1H-isoindole-2-base) piperidines-2, 6-diketone (compound 7 (a), 102 grams, 0.286 mole), yield 69%. 1H NMR(DMSO-d 6):δ1.40(s,9H),2.11-2.26(m,2H),2.69-2.84(m,2H),4.69-4.76(m,2H),5.11-5.15(m,1H),6.90-6.95(m,1H),7.65-7.71(m,1H),7.71-7.77(m,1H),10.95(br,1H).MS(m/z):360[M+H] +

Embodiment 11: ring-closure reaction

By obtained 2-brooethyl-3-tert.-butoxy formamide benzene methyl-formiate (compound 5 (a), 142 grams, 0.414 mole) and 3-amino-2, 6-dioxopiperidine hydrochloride (compound 6, 75 grams, 0.455 mole) be dissolved in N, dinethylformamide 800 milliliters, add triethylamine (173 milliliters, 1.242 mole), temperature control 60 degrees Celsius, stirring reaction 10 hours, be cooled to room temperature, pour in frozen water and stir 1 hour, filter, wash with water, dry, obtain 3-(7-tert.-butoxy formamido--3-oxo-1H-isoindole-2-base) piperidines-2, 6-diketone (compound 7 (a), 76 grams, 0.211 mole), yield 51%.MS(m/z):360[M+H] +

Embodiment 12: ring-closure reaction

By obtained 2-brooethyl-3-benzyloxy-formyl amine methyl benzoate (compound 5 (b), 132 grams, 0.350 mole) and 3-amino-2, 6-dioxopiperidine hydrochloride (compound 6, 63 grams, 0.385 mole) be dissolved in N, dinethylformamide 800 milliliters, add (144 grams, salt of wormwood, 1.050 mole), temperature control 60 degrees Celsius, stirring reaction 10 hours, be cooled to room temperature, pour in frozen water and stir 1 hour, filter, wash with water, dry, obtain 3-(7-benzyloxyformamido-3-oxo-1H-isoindole-2-base) piperidines-2, 6-diketone (compound 7 (b), 92 grams, 0.235 mole), yield 67%. 1H NMR(DMSO-d 6):δ2.13-2.20(m,2H),2.34-2.44(m,2H),4.29-4.35(m,2H),5.02-5.06(m,1H),5.21(s,2H),6.92-6.98(m,1H),7.17-7.29(m,5H),7.58-7.64(m,1H),7.71-7.76(m,1H),10.26(br,1H).MS(m/z):394[M+H] +

Embodiment 13: deprotection reaction

By 3-(7-tert.-butoxy formamido--3-oxo-1H-isoindole-2-base) piperidines-2, 6-diketone (compound 7 (a), 100 grams, 0.278 mole) be dissolved in tetrahydrofuran (THF) 1000 milliliters, temperature control less than 10 degrees Celsius slowly adds trifluoracetic acid 50 milliliters, temperature control 25 degrees Celsius, stirring reaction is after 6 hours, concentrating under reduced pressure removes most solvent, add saturated sodium bicarbonate aqueous solution 2000 milliliters, with dichloromethane extraction, with water, saturated sodium bicarbonate aqueous solution, saturated common salt water washing, dry, after concentrating under reduced pressure, available isopropyl alcohol and water recrystallization obtains Revlimid (63 grams, 0.245 mole), yield 88%. 1H NMR(DMSO-d 6):δ2.12-2.23(m,2H),2.72-2.95(m,2H),4.38-4.46(m,2H),5.12-5.15(m,1H),6.88-6.92(m,1H),7.00-7.07(m,1H),7.17-7.25(m,1H),10.93(br,1H).MS(m/z):260[M+H] +

Embodiment 14: deprotection reaction

By 3-(7-tert.-butoxy formamido--3-oxo-1H-isoindole-2-base) piperidines-2, 6-diketone (compound 7 (a), 100 grams, 0.278 mole) be dissolved in tetrahydrofuran (THF) 1000 milliliters, temperature control less than 10 degrees Celsius slowly adds the hydrochloric acid 80 milliliters of 2M, temperature control 25 degrees Celsius, stirring reaction is after 6 hours, concentrating under reduced pressure removes most solvent, add saturated sodium bicarbonate aqueous solution 2000 milliliters, with dichloromethane extraction, with water, saturated sodium bicarbonate aqueous solution, saturated common salt water washing, dry, after concentrating under reduced pressure, available isopropyl alcohol and water recrystallization obtains Revlimid (53 grams, 0.206 mole), yield 74%.MS(m/z):260[M+H] +

Embodiment 15: deprotection reaction

By 3-(7-tert.-butoxy formamido--3-oxo-1H-isoindole-2-base) piperidines-2, 6-diketone (compound 7 (a), 100 grams, 0.278 mole) be dissolved in tetrahydrofuran (THF) 1000 milliliters, temperature control less than 10 degrees Celsius slowly adds trifluoracetic acid 50 milliliters, temperature control 25 degrees Celsius, stirring reaction is after 6 hours, concentrating under reduced pressure removes most solvent, add saturated sodium bicarbonate aqueous solution 2000 milliliters, with dichloromethane extraction, with water, saturated sodium bicarbonate aqueous solution, saturated common salt water washing, dry, after concentrating under reduced pressure, available second alcohol and water recrystallization obtains Revlimid (55 grams, 0.214 mole), yield 77%.MS(m/z):260 [M+H] +

Embodiment 16: deprotection reaction

By 3-(7-benzyloxyformamido-3-oxo-1H-isoindole-2-base) piperidines-2, 6-diketone (compound 7 (b), 100 grams, 0.254 mole) be dissolved in methyl alcohol 1000 milliliters, add 10% palladium charcoal (Pd/C, 10g) with ammonium formiate (158g, 2.500 mole), nitrogen protection can be added, temperature control 25 ~ 35 degrees Celsius, stirring reaction 3 hours, suction filtration removing palladium charcoal, filtrate reduced in volume, with dichloromethane extraction, with water, saturated common salt water washing, dry, after concentrating under reduced pressure, available isopropyl alcohol and water recrystallization obtains Revlimid (56 grams, 0.216 mole), yield 85%.MS(m/z):260[M+H] +

In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " illustrative examples ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, identical embodiment or example are not necessarily referred to the schematic representation of above-mentioned term.And the specific features of description, structure, material or feature can combine in an appropriate manner in any one or more embodiment or example.

Although illustrate and describe embodiments of the invention above; be understandable that; above-described embodiment is exemplary; limitation of the present invention can not be interpreted as; those of ordinary skill in the art can change above-described embodiment within the scope of the invention when not departing from principle of the present invention and aim, revising, replacing and modification, and these all drop on the scope of the present invention.

Claims (26)

1. a method for compound shown in preparation formula 1, is characterized in that, comprising:
1) esterification of compound generation shown in formula 2 is made, to obtain compound shown in formula 3;
2) compound shown in described formula 3 is contacted with amino protecting agent, to obtain compound shown in formula 4;
3) compound generation halogenating reaction shown in described formula 4 is made, to obtain compound shown in formula 5;
4) compound shown in compound with formula 6 shown in described formula 5 is contacted, to obtain compound shown in formula 7; And
5) by compound generation deprotection reaction shown in described formula 7, to obtain compound shown in described formula 1,
Wherein, R1 is alkyl, and R2 is halogen, and PG represents amido protecting group,
In step 2) in, in the first organic solvent, when there is alkaline catalysts, compound shown in described formula 3 being contacted with described amino protecting agent, to carry out amido protecting reaction, thus obtaining compound shown in formula 4,
Wherein,
Described first organic solvent is at least one being selected from halogenated hydrocarbon organic solvent and ether organic solvent,
Wherein,
Described halogenated hydrocarbon organic solvent is at least one being selected from methylene dichloride and trichloromethane,
Described ether organic solvent is at least one being selected from tetrahydrofuran (THF), methyl tertiary butyl ether and dioxane,
Described alkaline catalysts is at least one being selected from DMAP and triethylamine,
Shown in described formula 3, the mol ratio of compound and described amido protecting agent is 1:1.1 ~ 2.0,
Shown in described formula 3, the mol ratio of compound and alkaline catalysts is 1:1.5 ~ 3.0,
Described amido protecting reaction carries out 3 ~ 8 hours at the temperature of 0 ~ 45 degree Celsius.
2. method according to claim 1, is characterized in that, R1 to be carbon atom number be 1 ~ 10 alkyl.
3. method according to claim 2, is characterized in that, R1 is methyl, and R2 is Br or Cl.
4. method according to claim 3, is characterized in that, R2 is Br.
5. method according to claim 1, is characterized in that, in step 1) in, when there is acid catalyst, compound shown in described formula 2 being contacted with monohydroxy-alcohol, there is described esterification, thus obtains compound shown in described formula 3.
6. method according to claim 5, is characterized in that, described acid catalyst is at least one being selected from tosic acid and sulfuric acid, described monohydroxy-alcohol to be carbon atom number be 1 ~ 10 monohydroxy-alcohol.
7. method according to claim 6, is characterized in that, described monohydroxy-alcohol is methyl alcohol.
8. method according to claim 5, is characterized in that, shown in described formula 2, the mol ratio of compound and described acid catalyst is 1:1.2 ~ 3.0.
9. method according to claim 5, is characterized in that, at the temperature of 50 ~ 80 degrees Celsius, carries out described esterification 8 ~ 15 hours.
10. method according to claim 1, is characterized in that, described amino protecting agent is be selected from least one in tert-Butyl dicarbonate, chloroformic acid benzyl ester, bromobenzyl and Tosyl chloride.
11. methods according to claim 10, is characterized in that, described amido protecting agent is be selected from least one in tert-Butyl dicarbonate and chloroformic acid benzyl ester.
12. methods according to claim 11, is characterized in that, described amido protecting agent is tert-Butyl dicarbonate.
13. methods according to claim 1, is characterized in that, in step 3) in, in a second organic solvent, when there is initiator, by compound and halogenating agent shown in described formula 4, to carry out halogenating reaction, thus generate compound shown in described formula 5
Wherein,
Described second organic solvent is at least one being selected from methyl chloride, methylene dichloride, trichloromethane, monochloroethane, ethylene dichloride and trichloroethane,
Described halogenating agent for being selected from least one in cupric bromide, hydrogen bromide, N-bromo-succinimide (NBS), bromination dimethyl bromo sulphur (DMBS), Sodium Bromide, Potassium Bromide, brometo de amonio and bromine chloride,
Described initiator is at least one being selected from Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile), benzoyl peroxide and di-isopropyl peroxydicarbonate.
14. methods according to claim 13, is characterized in that, described second organic solvent is be selected from least one in methylene dichloride and trichloromethane, and described halogenating agent is N-bromo-succinimide, and described initiator is Diisopropyl azodicarboxylate.
15. methods according to claim 14, it is characterized in that, shown in described formula 4, the mol ratio of compound and described halogenating agent is 1:1.05 ~ 2.0, shown in described formula 4, the mol ratio of compound and described initiator is 1:0.1 ~ 0.5, and described halogenating reaction carries out 3 ~ 8 hours at the temperature of 30 ~ 80 degrees Celsius.
16. methods according to claim 1, is characterized in that, in step 4) in, in the 3rd organic solvent, when there is basic cpd, compound shown in compound with formula 6 shown in formula 5 is contacted, there is ring-closure reaction, thus compound shown in production 7
Wherein,
Described 3rd organic solvent is for being selected from least one in DMF (DMF) and N,N-dimethylacetamide, and described basic cpd is at least one being selected from organic bases and mineral alkali.
17. methods according to claim 16, is characterized in that, described 3rd organic solvent is DMF, and described basic cpd is at least one being selected from salt of wormwood and triethylamine.
18. methods according to claim 17, it is characterized in that, in step 4) in, shown in described formula 5, shown in compound and described formula 6, the mol ratio of compound is 1:1.0 ~ 1.5, shown in described formula 5, the mol ratio of compound and described basic cpd is 1:1.5 ~ 3.5, and described ring-closure reaction carries out 8 ~ 16 hours at the temperature of 50 ~ 100 degrees Celsius.
19. methods according to claim 1, is characterized in that, in step 5) in, in the 3rd organic solvent, when there is acid, make compound generation deprotection reaction shown in described formula 7, so that compound shown in production 1,
Wherein, described 3rd organic solvent is at least one of methyl chloride, methylene dichloride, trichloromethane, monochloroethane, ethylene dichloride and trichloroethane, methyl ether, ether, sherwood oil, isopropyl ether, methyl tertiary butyl ether, ethyl-butyl ether, Ethyl Tertisry Butyl Ether, tetrahydrofuran (THF), tetrahydropyrans, dioxane and methyl-phenoxide, and described acid is for being selected from least one in organic acid and mineral acid.
20. methods according to claim 19, is characterized in that, described 3rd organic solvent is be selected from least one in methylene dichloride and trichloromethane, sherwood oil, tetrahydrofuran (THF), methyl tertiary butyl ether and dioxane,
Described acid is for being selected from least one of trifluoracetic acid, hydrochloric acid, trifluoromethanesulfonic acid and p-methyl benzenesulfonic acid.
21. methods according to claim 20, is characterized in that, shown in described formula 7, the mol ratio of compound and described acid is 1:0.5 ~ 2.5, and described deprotection reaction carries out 5 ~ 10 hours under 0 ~ 35 degree Celsius.
22. methods according to claim 1, is characterized in that, in step 5) in, in the 4th organic solvent, when there is palladium and ammonium formiate, make compound generation deprotection reaction shown in described formula 7, so that compound shown in production 1,
Wherein, described 4th organic solvent is at least one being selected from methyl alcohol, ethanol, propyl alcohol, butanols and ethylene glycol, methyl ether, ether, sherwood oil, isopropyl ether, methyl tertiary butyl ether, ethyl-butyl ether, Ethyl Tertisry Butyl Ether, tetrahydrofuran (THF), tetrahydropyrans, dioxane and methyl-phenoxide.
23. methods according to claim 22, is characterized in that, described 4th organic solvent is be selected from least one in methyl alcohol, sherwood oil, tetrahydrofuran (THF), methyl tertiary butyl ether and dioxane.
24. methods according to claim 23, is characterized in that, described palladium provides with palladium charcoal form, and described deprotection reaction carries out 2 ~ 6 hours at the temperature of 20 ~ 60 degrees Celsius.
25. methods according to claim 1, is characterized in that, described deprotection reaction carries out in an inert atmosphere.
26. methods according to claim 25, is characterized in that, described inert atmosphere is made up of at least one be selected from nitrogen and argon gas.
CN201310472457.8A 2013-03-14 2013-10-11 Prepare the method for Revlimid CN103497175B (en)

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US7153867B2 (en) * 2001-08-06 2006-12-26 Celgene Corporation Use of nitrogen substituted thalidomide analogs for the treatment of macular degenerator
CN101959856A (en) * 2008-03-11 2011-01-26 雷迪博士实验室有限公司 Preparation of lenalidomide

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US7153867B2 (en) * 2001-08-06 2006-12-26 Celgene Corporation Use of nitrogen substituted thalidomide analogs for the treatment of macular degenerator
CN101959856A (en) * 2008-03-11 2011-01-26 雷迪博士实验室有限公司 Preparation of lenalidomide

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