LV14985B - Method for production of lenalidomide - Google Patents
Method for production of lenalidomide Download PDFInfo
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- LV14985B LV14985B LVP-13-152A LV130152A LV14985B LV 14985 B LV14985 B LV 14985B LV 130152 A LV130152 A LV 130152A LV 14985 B LV14985 B LV 14985B
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- dione
- lenalidomide
- piperidine
- dihydro
- oxo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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[0001] Izgudrojums attiecas uz farmakoloģiski aktīvas vielas iegūšanas procesu. Konkrētāk, izgudrojums attiecas uz pretvēža preparāta lenalidomīda iegūšanas procesu.The invention relates to a process for obtaining a pharmacologically active substance. More particularly, the invention relates to a process for the preparation of an anticancer agent lenalidomide.
[0002] Lenalidomīds jeb (RS)-3-(4-amino-1-okso-1,3-dihidro-2H-izoindol-2il)piperidīn-2,6-dions (I) ir imunomodulators, kas paredzēts dažādu melanomas veidu, ka arī dažu mielodisplastiskā sindroma paveidu izraisošo anēmiju ārstēšanai [1].Lenalidomide, or (RS) -3- (4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione (I), is an immunomodulator for various types of melanoma. , and also for the treatment of some types of anemia causing myelodysplastic syndrome [1].
[0003] Lenalidomīda (I) iegūšanas būtiskās stadijas ir 2-metil-3nitrobenzoskābes metilestetra (II) bromēšana par 2-(brommetil)-3nitrobenzoskābes metilesteri (lll) un 3-(4-nitro-1-okso-1,3-dihidro-2H-izoindol2-il)piperidīn-2,6-diona (IV) nitro grupas reducēšana.The essential steps in the preparation of lenalidomide (I) are the bromination of 2-methyl-3-nitrobenzoic acid methyl ester (II) to 2- (bromomethyl) -3-nitrobenzoic acid methyl ester (III) and 3- (4-nitro-1-oxo-1,3-dihydro) -2H-isoindol2-yl) piperidine-2,6-dione (IV) nitro reduction.
[0004] Zināmie lenalidomīda starpprodukta (lll) iegūšanas paņēmieni ir bromēšana pēc brīvo radikāļu mehānisma, kas parasti notiek temperatūras diapazonā 90-140 °C, izmantojot broma avotu (broms vai Nbromsukcīnimīds) un radikāļu iniciatoru - benzoilperoksīdu [1,2], 2,2'azobisizobutironitrilu [3, 21]), gaismu [4] vai radikāļu iniciatora un gaismasKnown methods for preparing the lenalidomide intermediate (III) include bromination by a free radical mechanism which typically occurs at a temperature in the range of 90-140 ° C using a bromine source (bromine or Nbromosuccinimide) and a radical initiator, benzoyl peroxide [1,2], 2, 2'azobisisobutyronitrile [3, 21]), light [4] or radical initiator and light
-2apvienojumu [5]. Reakcijas veiksmīgai norisei nepieciešami inerti hloru saturošie šķīdinātāji - tetrahlorogleklis, hlorbenzols, dihlorbenzols, dihlormetāns, dihloretāns vai hloroforms. Zināms, ka šie šķīdinātāji ir bīstami veselībai un apkārtējai videi, to cena salīdzinoši ar hloru nesaturošiem šķīdinātājiem ir augstāka, tie rada lielus izdevumus utilizācijā un vides piesārņojuma kontrolē.-2 combination [5]. The reaction requires inert chlorine-containing solvents such as carbon tetrachloride, chlorobenzene, dichlorobenzene, dichloromethane, dichloroethane or chloroform. These solvents are known to be hazardous to health and the environment, and have a higher cost compared to chlorine-free solvents and cause high costs for disposal and environmental pollution control.
[0005] Lenalidomīdu praktiski visizdevīgāk iegūt no 3-(4-nitro-1-okso-1,3dihidro-2H-izoindol-2-il)piperidīn-2,6-diona (IV). Izplatītākais veids, kā to veikt, ir nitrogrupas reducēšana ar katalītisko hidrogenēšanu [6-15, 23].[0005] Lenalidomide is practically most advantageously obtained from 3- (4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione (IV). The most common way to do this is by reduction of the nitro group with catalytic hydrogenation [6-15, 23].
[0006] Katalītiskajā hidrogenēšanā nepieciešams lietot pārejas metālu katalizatorus (Pd/C, PtO2) un ūdeņradi. Tas sadārdzina produkta iegūšanu, jo nepieciešams ierīkot specializētas hidrogenēšanas iekārtas un drošības ierīces hidrogenēšanai ar sprādzienbīstamu gāzi. Gala produktā nepieciešams kontrolēt smago metālu piemaisījumu daudzumu. Reakcijas apstākļos rodas nitro grupas daļējas reducēšanas produkti un reducēšanas starpprodukta - nitrozosavienojuma diproporcionēšanās produkti. Produkta attīrīšana no radniecīgas struktūras blakusproduktiem ir sarežģīts process, kas negatīvi ietekmē produkta iznākumus un sadārdzina procesu.[0006] Catalytic hydrogenation requires the use of transition metal catalysts (Pd / C, PtO 2 ) and hydrogen. This makes the production of the product more expensive as it requires the installation of specialized hydrogenation equipment and safety devices for the hydrogenation of explosive gas. Heavy metal impurities need to be controlled in the final product. Reaction conditions give rise to partial reduction products of the nitro group and diproportionation products of the reduction intermediate nitroso compound. Purifying a product from a by-product of a related structure is a complex process that adversely affects product performance and makes the process more expensive.
[0007] Cits zināms nekatalītisks lenalidomīda iegūšanas paņēmiens ir nitrosavienojuma (IV) reducēšana ar dzelzi sālsskābē, iegūstot lenalidomīda hidrohlorīdu (V), kuru apstrādājot ar amonjaka ūdens šķīdumu, iegūst lenalidomīdu (I) [20].Another known non-catalytic method for preparing lenalidomide is by reduction of the nitro compound (IV) with iron in hydrochloric acid to give lenalidomide hydrochloride (V) which is treated with aqueous ammonia to produce lenalidomide (I) [20].
[0008] 3-(4-Nitro-1-okso-1,3-dihidro-2H-izoindol-2-il)piperidīn-2,6-dionu (IV) iegūst ar dažādām metodēm. Publikācijās [22, 23], kā arī patentos [16-19] lenalidomīda starpproduktu (IV) iegūst ciklizācijas ceļā no 2-(brommetil)-3nitrobenzoskābes metilestera (III) un 3-aminopiperidīn-2,6-diona (V).3- (4-Nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione (IV) is obtained by various methods. In publications [22, 23] and in patents [16-19], the lenalidomide intermediate (IV) is obtained by cyclization from 2- (bromomethyl) -3-nitrobenzoic acid methyl ester (III) and 3-aminopiperidine-2,6-dione (V).
2 (iv) [0009] Patentā [11] aprakstīts cits lenalidomīda starpprodukta (IV) sintēzes ceļš, izmantojot dažādus glutamīna un glutamīnskābes atvasinājumus (VI), kuru reakcijas rezultātā ar 2-(brommetil)-3-nitrobenzoskābes metilesteri (III) iegūst savienojumus (VII), kuri pēc tam tiek ciklizēti par lenalidomīda starpproduktu (IV). 2 (iv) Another patent [11] describes another route for the synthesis of lenalidomide intermediate (IV) using various derivatives of glutamine and glutamic acid (VI) which react with 2- (bromomethyl) -3-nitrobenzoic acid methyl ester (III). (VII), which are then cyclized to the lenalidomide intermediate (IV).
R = OH, OMe, NH2 R = OH, OMe, NH 2
Tātad no 2-metil-3-nitrobenzoskābes metilestera (II) lenalidomīdu var iegūt minimums četrās stadijās.Thus, lenalidomide of 2-methyl-3-nitrobenzoic acid methyl ester (II) can be obtained in a minimum of four steps.
[0010] Cits ceļš, kas ir garāks un praktiski mazāk izdevīgs, ir aprakstīts patentā [8]. Sintēzes ceļš iekļauj 2-(brommetil)-3-nitrobenzo-skābes metilestera (III) ciklizāciju un nitrogrupas reducēšanu, iegūstot 4aminoizoindolīn-1-onu (VIII). Veicot aminogrupas aizsargāšanu un amīda alkilēšanu ar 2-bromglutarskābes atvasinājumiem, iegūst savienojumu (IX), kuru ciklizē un nošķeļ aizsargrupu, iegūstot lenalidomīdu (I). Viena no piemērotākajām aizsarggrupām šādās reakcijās, ko lieto arī patentā [8], ir benziloksikarbonilgrupa (Cbz), kuras nošķelšanai tiek izmantota katalītiska hidrogenēšana.Another route, which is longer and practically less advantageous, is described in the patent [8]. The synthesis pathway involves cyclization of the 2- (bromomethyl) -3-nitrobenzoic acid methyl ester (III) and reduction of the nitro group to give 4 aminoisoindolin-1-one (VIII). Protection of the amino group and alkylation of the amide with 2-bromo-glutaric acid derivatives affords compound (IX), which is cyclized and cleaves to give lenalidomide (I). One of the most suitable protecting groups for such reactions, which is also used in the patent [8], is benzyloxycarbonyl (Cbz), which is cleaved by catalytic hydrogenation.
-4·-4 ·
R = ΟΗ, OMe, ΝΗ2; PG - aizsarggrupa (Cbz vai cita) [0011] Kā redzams no iepriekšējām shēmām, 2-(brommetil)-3nitrobenzoskābes metilesteris (III) ir svarīgākais starpprodukts lenalidomīda iegūšanai neatkarīgi no sintēzes ceļa. Ņemot vērā, ka šis savienojums tiek sintezēts tehnoloģiskā procesa sākumposmā, tas jāsintezē lielākos apjomos, kas paredz arī lielu halogēnsaturošo šķīdinātāju daudzumu lietošanu. Tas sadārdzina lenalidomīda iegūšanas procesu, palielinot izmaksas šķīdinātāju iegādei un utilizācijai, un liek meklēt citas sintēzes metodes, kas padarītu procesu lētāku un ekoloģiski tīrāku, bet gala produktu - lenalidomīdu attiecīgi vairāk pieejamu vēža slimniekiem.R = ΟΗ, OMe, ΝΗ 2 ; PG - protecting group (Cbz or other) As can be seen from the above schemes, 2- (bromomethyl) -3-nitrobenzoic acid methyl ester (III) is the most important intermediate for the preparation of lenalidomide, irrespective of the route of synthesis. Since this compound is synthesized at an early stage of the technological process, it should be synthesized in larger quantities, which also requires the use of large amounts of halogen-containing solvents. This makes the process of obtaining lenalidomide more expensive, increasing the cost of purchasing and disposing of solvents, and calls for other methods of synthesis that would make the process cheaper and more environmentally friendly, while making the end product lenalidomide more accessible to cancer patients.
[0012] Lenalidomīds, kas iegūts, hidrogenējot 3-(4-nitro-1-okso-1,3-dihidro2H-izoindol-2-il)piperidīn-2,6-dionu (IV) ar ūdeņradi pārejas metālu klātienē, parasti satur ievērojamu daudzumu daļējas hidrogenēšanas un nitrozo starpsavienojuma disproporcionēšanās produktu, kā arī pārejas metālu piemaisījumus. Lai iegūtu farmaceitiskas kvalitātes produktu, tas vairākkārt jāpārkristalizē, vai arī jāpārvērš par sāli un tad pēc sāls attīrīšanas atkal par bāzi. Sevišķas grūtības sagādā attīrīšana no metālu piemaisījumiem, jo to pieļaujamā koncentrācija gala produktā mērojama miljonajās daļās.Lenalidomide obtained by hydrogenation of 3- (4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione (IV) with hydrogen in the presence of a transition metal usually contains significant amounts of products of partial hydrogenation and disproportionation of the nitroso intermediate as well as transition metal impurities. To obtain a pharmaceutical grade product, it must be recrystallized several times or converted to salt and then, after purification of the salt, to the base again. Particularly difficult is the purification of metallic impurities since their permissible concentration in the final product is in millions of parts.
[0013] Savukārt veicot 3-(4-nitro-1-okso-1,3-dihidro-2H-izoindol-2-il)piperidīn2,6-diona (IV) reducēšanu ar dzelzi sālsskābē, tiek iegūts lenalidomīda hidrohlorīds, kas labi šķīst ūdenī un ir grūti atdalāms no dzelzs sāļiem. Šajā gadījumā, lai iegūtu lenalidomīdu bāzes formā, nepieciešams neitralizēt tāConversely, reduction of 3- (4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione (IV) with iron in hydrochloric acid yields lenalidomide hydrochloride which is well soluble in water and difficult to separate from iron salts. In this case, it is necessary to neutralize lenalidomide in its base form
-5hidrohlorīdu ar stiprāku bāzi, bet šo procesu apgrūtina liels dzelzs hidroksīda daudzums, kas rodas neitralizēšanas laikā. Visas šīs papildus procedūras produkta attīrīšanai samazina tā iznākumu un sadārdzina tehnoloģisko procesu.-5hydrochloride with a stronger base, but this process is complicated by the large amount of ferric hydroxide produced during the neutralization. All these additional procedures to purify the product reduce its performance and make the process more expensive.
IZGUDROJUMA KOPSAVILKUMS [0014] Mēs negaidīti atklājām, ka zināmo lenalidomīda iegūšanas procesu var uzlabot ar jauniem 2-(brommetil)-3-nitrobenzoskābes metilestera (III) un galaprodukta iegūšanas paņēmieniem.SUMMARY OF THE INVENTION We have unexpectedly discovered that the known process for preparing lenalidomide can be improved by novel processes for the preparation of 2- (bromomethyl) -3-nitrobenzoic acid methyl ester (III) and the final product.
[0015] 2-(brommetil)~3-nitrobenzoskābes metilesteri (III) iespējams iegūt no 2metil-3-nitrobenzoskābes metilestera (II), izmantojot halogēnus nesaturošu šķīdinātāju - metilacetātu. Atklātajai metodei ir vairākas priekšrocības: process notiek salīdzinoši zemā temperatūrā (57 °C), produkts rodas ar gandrīz kvantitatīvu iznākumu un tam ir augsta tīrība bez papildus attīrīšanas (98% pēc AEŠH datiem). Ņemot vērā ka 2-(brommetil)-3-nitrobenzoskābes metilesteris (III) ir neaizstājama izejviela lenalidomīda sintēzē, šī metode ļauj būtiski samazināt videi nedraudzīgo šķīdinātāju lietošanu šajā procesā, izvairīties no drošības pasākumiem, kas saistīti arto lietošanu un utilizāciju, un attiecīgi samazināt kopējās sintēzes izmaksas. Metilacetāts praktiski nav pētīts un lietots kā radikāļu bromēšanas reakciju Sludinātājs.2- (Bromomethyl) -3-nitrobenzoic acid methyl ester (III) can be obtained from 2-methyl-3-nitrobenzoic acid methyl ester (II) using a halogen-free solvent, methyl acetate. The disclosed method has several advantages: the process is carried out at relatively low temperatures (57 ° C), the product is almost quantitatively yielded and has a high purity without further purification (98% by HPLC). Given that 2- (bromomethyl) -3-nitrobenzoic acid methyl ester (III) is an indispensable starting material for the synthesis of lenalidomide, this method significantly reduces the use of environmentally unfriendly solvents in this process, avoids the precautionary measures associated with the use and disposal, cost of synthesis. Methyl acetate has been virtually unexplored and used as a radical brominator.
[0016] Mēs arī negaidīti atklājām, ka galaproduktu - lenalidomīdu - iespējams iegūt, reducējot 3-(4-nitro-1-okso-1,3-dihidro-2H-izoindol-2-il)piperidīn-2,6dionu (IV), izmantojot amonija hlorīdu un dzelzi. Pārsteidzoši, ka dzelzs un amonija hlorīda sistēmā iegūtajam lenalidomīdam ir ļoti zems piemaisījumu saturs (AEŠH tīrība 98%), pie tam tas veidojas bāzes formā, kas nav iespējams, lietojot sistēmu metāls-skābe. Izgudrojuma priekšrocības ir zemas izmaksas (dzelzs un amonija hlorīds ir ļoti lēti un viegli uzglabājami reaģenti), īss reakcijas laiks (4 st.) un augsta efektivitāte (produkts rodas ar augstu iznākumu, tehniskā produkta tīrība ~98%). Šādai reducēšanas metodei nav raksturīga ciklu atvēršanās. Veicot vienkāršu pārkristalizāciju, ir iespējams iegūt farmaceitiskas tīrības produktu ar kopējo reakcijas iznākumu -80%.We have also unexpectedly discovered that the final product, lenalidomide, can be obtained by reduction of 3- (4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione (IV). using ammonium chloride and iron. Surprisingly, lenalidomide from the iron and ammonium chloride system has a very low impurity content (98% purity of AESH), and is formed in a basic form which is not possible with the metal-acid system. Advantages of the invention are low cost (iron and ammonium chloride are very cheap and easy to store reagents), short reaction time (4 hours) and high efficiency (high yield product, purity of technical product ~ 98%). This reduction method is not characterized by cycle opening. By simple recrystallization it is possible to obtain a pharmaceutical purity product with a total reaction yield of -80%.
PIEMĒRIEXAMPLES
1. piemērs.Example 1:
[0017] 2-(brommetil)-3-nitrobenzoskābes metilestera iegūšanaPreparation of 2- (bromomethyl) -3-nitrobenzoic acid methyl ester
Ar atteces dzesinātāju un mehānisko maisītāju aprīkotā reaktorā iekrauj 100,0 g (0,51 mol) 2-metil-3-nitrobenzoskābes metilestera, pievieno 134,0 g (0,75 mol) N-bromsukcinimīda un pielej 1,0 L metilacetāta. Iegūtajai suspensijai pievieno 8,4 g (0,05 mol) 2,2'-azobisizobutironitrila un maisot vāraIn a reactor equipped with a reflux condenser and a mechanical stirrer, 100.0 g (0.51 mol) of methyl 2-methyl-3-nitrobenzoic acid are charged, 134.0 g (0.75 mol) of N-bromosuccinimide are added and 1.0 L of methyl acetate is added. To the resulting suspension add 8.4 g (0.05 mol) of 2,2'-azobisisobutyronitrile and stir
18 st. (reakcijas temperatūra 57 °C). Pēc tam reakcijas masu atdzesē, mazgā ar 10% Na2SO3 ūdens šķīdumu, tad ar 10% NaCI ūdens šķīdumu. Organisko slāni filtrē, ietvaicē un uzreiz pēc ietvaicēšanas pie iegūtās oranži dzeltenās eļļas pievieno 90 mL izopropolspirta un ūdens maisījuma (2:1), un maisa istabas temperatūrā. Maisīšanas laikā produkts sakristalizējas. Nogulsnes nofiltrē, žāvē 6 st. pie 50-55 °C vakuumā (10-20 mbar). Iznākums 138,0 g (98%), gaiši dzelteni kristāli. Tīrība pēc AEŠH - 98%.18 hours (reaction temperature 57 ° C). The reaction mass is then cooled, washed with 10% aqueous Na 2 SO 3 , then with 10% aqueous NaCl. The organic layer is filtered, evaporated and immediately after evaporation, 90 mL of a 2: 1 mixture of isopropanol and water (2: 1) are added to the resulting orange-yellow oil and stirred at room temperature. The product crystallizes during mixing. The precipitate is filtered off and dried for 6 hours. at 50-55 ° C under vacuum (10-20 mbar). Yield 138.0 g (98%), light yellow crystals. Purity by HPLC - 98%.
2. piemērs.Example 2:
[0018] Lenalidomīda iegūšanaPreparation of lenalidomide
Reaktorā 580 mL ūdens izšķīdina 95,6 g (1,76 mol) NH4CI, tad pievieno 65,0 g (0,22 mol) 3-(4-nitro-1-okso-1,3-dihidro-2/7-izoindol-2-il)piperidīn-2,6diona un 2,9 L etanola. Reakcijas maisījumu uzsilda līdz 60 °C, maisot pievieno 49,0 g (0,88 mol) dzelzs pulvera. Maisījumu silda pie 80 °C 4 st. Reakcijas maisījumu nofiltrē karstu, nogulsnes divas reizes mazgā ar 200 mL karsta etanola-ūdens šķīduma (50 mL ūdens + 150 mL etanola). Filtrātu ietvaicē, sausajam atlikumam pievieno 200 mL ūdens, maisa 30 min, nogulsnes filtrē un skalo divreiz ar 50 mL ūdens. Tehnisko produktu vāra 2,5 st. ar 900 mL etanola un 600 mL ūdens maisījumu, pievieno 6 g aktivētās ogles un vāra vēl 1 st. Karsto maisījumu filtrē. Filtrātam ļauj kristalizēties pieDissolve 95.6 g (1.76 mol) of NH4Cl in 580 mL of water in the reactor, then add 65.0 g (0.22 mol) of 3- (4-nitro-1-oxo-1,3-dihydro-2/7) isoindol-2-yl) piperidine-2,6-dione and 2.9 L ethanol. The reaction mixture is heated to 60 ° C with the addition of 49.0 g (0.88 mol) of iron powder. The mixture is heated at 80 ° C for 4 h. The reaction mixture is filtered hot, the precipitate is washed twice with 200 mL of hot ethanol-water solution (50 mL of water + 150 mL of ethanol). The filtrate is evaporated, 200 mL of water is added to the dry residue, stirred for 30 min, the precipitate is filtered off and rinsed twice with 50 mL of water. The technical product is cooked for 2.5 hours. with a mixture of 900 mL of ethanol and 600 mL of water, add 6 g of activated carbon and boil for another 1 h. The hot mixture is filtered. The filtrate is allowed to crystallize out at 100
-70-5 °C, nogulsnes nofiltrē. Produktu žāvē 6 st. pie 60 °C 15-20 mbar spiedienā. Iznākums 47,6 g (84%) gaiši dzeltenas vielas. Tīrība pēc AEŠH 99,8%.-70-5 ° C, the precipitate is filtered off. The product is dried for 6 hours. at 60 ° C at a pressure of 15-20 mbar. Yield: 47.6 g (84%) of a pale yellow substance. Purity by HPLC 99.8%.
[0019] Nepieciešamības gadījumā produktu iespējams pārkristalizēt no ūdens, metanola, acetona vai citiem šķīdinātājiem, iegūstot nepieciešamo polimorfo formu.If necessary, the product can be recrystallized from water, methanol, acetone or other solvents to give the desired polymorphic form.
[0020] Paņēmieni ir realizējami rūpnieciskā ražošanā, iegūstot svarīgu farmaceitiski aktīvu vielu dažādu vēža formu ārstēšanai ar ekonomiski izdevīgām un videi draudzīgām metodēm.The methods are commercially available, providing an important pharmaceutically active substance for the treatment of various cancers by cost-effective and environmentally friendly methods.
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17. WO2011/27326A1,201117. WO2011 / 27326A1,2011
18. WO2011/111053A1, 201118. WO2011 / 111053A1, 2011
19. US2012/71509A1, 201219. US2012 / 71509A1, 2012
20. WO2010/61209 A1, 201020. WO2010 / 61209 A1, 2010
Pārēja literatūra:Other literature:
21. Bioorg. Med. Chem. Lett., 14, 81 (2004).21. Bioorg. Med. Chem. Lett., 14, 81 (2004).
22. Bioorg. Med. Chem. Lett., 9,1625 (1999).22. Bioorg. Med. Chem. Lett., 1999, 9,1625.
23. Bioorg. Med. Chem. Lett., 3,1019 (2011).23. Bioorg. Med. Chem. Lett., 3,1019 (2011).
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| LVP-13-152A LV14985B (en) | 2013-10-14 | 2013-10-14 | Method for production of lenalidomide |
| PCT/LV2014/000010 WO2015057043A1 (en) | 2013-10-14 | 2014-10-03 | A process for the preparation of lenalidomide |
| GB1522674.9A GB2535004B (en) | 2013-10-14 | 2014-10-03 | A process for the preparation of Lenalidomide |
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| LVP-13-152A LV14985B (en) | 2013-10-14 | 2013-10-14 | Method for production of lenalidomide |
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| LV14985B true LV14985B (en) | 2015-06-20 |
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| ES2733813T3 (en) * | 2014-08-19 | 2019-12-03 | Synthon Bv | Process to prepare a crystalline form of lenalidomide |
| CN109400579B (en) * | 2017-08-18 | 2020-06-23 | 新发药业有限公司 | Production method of lenalidomide |
| CN107337666B (en) * | 2017-08-30 | 2019-06-04 | 上海万巷制药有限公司 | It is a kind of for treating the preparation method of the lenalidomide of Huppert's disease |
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| DE69413183T2 (en) | 1993-06-25 | 1999-02-11 | Ihara Chemical Industry Co., Ltd., Tokio/Tokyo | INDAZOLSULFONYL URINE DERIVATIVE, USE AND INTERMEDIATE PRODUCTS FOR PRODUCTION |
| US6281230B1 (en) | 1996-07-24 | 2001-08-28 | Celgene Corporation | Isoindolines, method of use, and pharmaceutical compositions |
| EP1423115B9 (en) | 2001-08-06 | 2009-09-02 | The Children's Medical Center Corporation | Antiangiogenic activity of nitrogen substituted thalidomide analogs |
| JPWO2006080450A1 (en) * | 2005-01-27 | 2008-06-19 | 協和醗酵工業株式会社 | IGF-1R inhibitor |
| DE102006025317A1 (en) | 2006-05-31 | 2007-12-06 | Bayer Healthcare Aktiengesellschaft | Isoindolin-1-one, isoindolin-3-one and isoindoline-1,3-dione derivatives and their use |
| US20110021567A1 (en) | 2008-03-11 | 2011-01-27 | Dr. Reddy's Laboratories Ltd. | Preparation of lenalidomide |
| JP2012507496A (en) | 2008-11-03 | 2012-03-29 | ジェネリクス・（ユーケー）・リミテッド | Crystalline form of lenalidomide and process for its preparation |
| EA201391720A1 (en) | 2008-11-14 | 2014-04-30 | Консерт Фармасьютикалс Инк. | SUBSTITUTED DIOXOPIPERIDINYL-PHTHALIMIDE DERIVATIVES |
| EP2350055A4 (en) | 2008-11-17 | 2012-04-18 | Reddys Lab Ltd Dr | Lenalidomide solvates and processes |
| WO2010100476A2 (en) | 2009-03-02 | 2010-09-10 | Generics [Uk] Limited | Improved process |
| CN101580501B (en) | 2009-06-01 | 2011-03-09 | 南京卡文迪许生物工程技术有限公司 | Synthetic method of 3-(substituted dihydro-isoindolone-2-group)-2,6-dioxopiperidine and intermediate thereof |
| AU2010290822A1 (en) | 2009-09-03 | 2012-03-29 | Ranbaxy Laboratories Limited | Process for the preparation of lenalidomide |
| WO2011050962A1 (en) | 2009-10-29 | 2011-05-05 | Ratiopharm Gmbh | Acid addition salts of lenalidomide |
| WO2011069608A1 (en) | 2009-12-09 | 2011-06-16 | Ratiopharm Gmbh | S-lenalidomide, polymorphic forms thereof and blend comprising s- und r-lenalidomide |
| ES2727705T3 (en) | 2010-03-08 | 2019-10-18 | Natco Pharma Ltd | Form I anhydrous lenalidomide |
| MX2012010367A (en) | 2010-03-12 | 2012-11-23 | Celgene Corp | Methods for the treatment of non-hodgkin's lymphomas using lenalidomide, and gene and protein biomarkers as a predictor. |
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