LV14985B - Method for production of lenalidomide - Google Patents

Method for production of lenalidomide Download PDF

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Publication number
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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LV
Latvia
Prior art keywords
dione
lenalidomide
isoindol
piperidine
dihydro
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LVP-13-152A
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Latvian (lv)
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LV14985A (en
Inventor
Ivars KALVIŅŠ
Jurijs PONOMARJOVS
Larisa Varačeva
Aleksandrs ČERNOBROVIJS
Antons ĻEBEDEVS
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Latvijas Organiskās Sintēzes Institūts
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Priority to LVP-13-152A priority Critical patent/LV14985B/en
Publication of LV14985A publication Critical patent/LV14985A/en
Publication of LV14985B publication Critical patent/LV14985B/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/04Heterocyclic 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

Description

LV 14985

DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION AND TECHNICAL FIELD [0001] The invention relates to a process for obtaining a pharmacologically active substance. In particular, the invention relates to a process for the preparation of the anticancer lenalidomide.

Lenalidomide or (S) -3- (4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione (I) is an immunomodulator that for the treatment of various types of melanoma as well as some types of anemia causing myelodysplastic syndrome [1].

Essential stages of obtaining Lenalidomide (I) are bromination of 2-methyl-3-15 nitrobenzoic acid methyl ester (II) to 2- (bromomethyl) -3-nitrobenzoic acid methyl ester (III) and 3- (4-nitro-1-oxo-methyl) Reduction of 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione (IV) nitro.

Known techniques for obtaining lenalidomide intermediate (III) are bromination by a free radical mechanism typically occurring in the temperature range of 90-140 ° C using a bromine source (bromine or N-bromocinimide) and a radical initiator - benzoyl peroxide [1,2] , 2,2'-azobisisobutyronitrile [3, 21]), light [4] or a combination of radical initiator and light -2- [5]. Successful reaction requires inert chlorine-containing solvents such as carbon tetrachloride, chlorobenzene, dichlorobenzene, dichloromethane, dichloroethane or chloroform. It is known that these solvents are hazardous to health and the environment, their price is higher than that of non-chlorine 5 solvents, they generate high costs for disposal and control of environmental pollution.

Lenalidomide is 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 to reduce the nitro group by catalytic hydrogenation [6-15, 23].

Catalytic hydrogenation requires the use of transition metal catalysts (Pd / C, PtO2) and hydrogen. This increases the cost of obtaining the product, as 15 need to install specialized hydrogenation equipment and safety devices for hydrogenation with explosive gas. The final product needs to control the amount of heavy metal impurities. Under the reaction conditions, partial reduction products of the nitro group and dipropionation products of the nitroso compound of reduction are formed. Removing product 20 from related structure by-products is a complex process that adversely affects product outcomes and makes the process more expensive.

Another known non-catalytic method of obtaining lenalidomide is the reduction of the nitro compound (IV) with iron in hydrochloric acid to give lenalidomide hydrochloride (V) which, when treated with aqueous ammonia, yields 25 lenalidomide (I) [20].

3- (4-Nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione (IV) is obtained by various methods. In the publications [22, 23], as well as in patents [16-19], lenalidomide intermediate (IV) is obtained by cyclization from 2- (bromomethyl) -3-nitrobenzoic acid methyl ester (III) and 3-aminopiperidine-2,6-dione (V). . -3-

The patent [11] describes another route of synthesis of lenalidomide intermediate (IV) using a variety of glutamine and glutamic acid derivatives (VI), which result in the formation of compounds by methyl ester (III) of 2- (bromomethyl) -3-nitrobenzoic acid (III). Vil) which are then cyclized to the lenalidomide intermediate (IV).

R = OH, OMe, NH2 Thus, the lenalidomide of 2-methyl-3-nitrobenzoic acid methyl ester (II) can be obtained in a minimum of 10 in four steps.

Another path that is longer and less advantageous is described in the patent [8]. The synthesis pathway involves cyclization of methyl 2- (bromomethyl) -3-nitrobenzoic acid (III) and reduction of the nitro group to give 4-aminoisoindoline-1-one (VIII). By protecting the amino group and alkylating the amide with 2-bromobutaric acid derivatives, a compound (IX) is cyclized and cleaved off to form a lenalidomide (I). One of the most suitable protecting groups for such reactions, which are also used in the patent [8], is benzyloxycarbonyl (Cbz), whose catalytic hydrogenation is used for cleavage. 20 -4-

(πΐ) (v. >

R = OH, OMe, NH2; PG - protecting group (Cbz or other) As can be seen from the previous schemes, 2- (bromomethyl) -3-nitrobenzoic acid methyl ester (III) is the most important intermediate for the preparation of lenalidomide 5, regardless of the pathway of synthesis. Given that this compound is synthesized in the early stages of the technological process, it needs to be synthesized in larger quantities, which also requires the use of large amounts of halogen-containing solvents. It makes the process of obtaining lenalidomide more expensive by increasing the cost of purchasing and disposing of solvents, and makes it search for other methods of synthesis that would make 10 processes cheaper and more environmentally friendly, and the final product - lenalidomide - more appropriately available for cancer patients.

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 transition metals, \ t usually contains significant amounts of partial hydrogenation and nitroso-intermediate disproportionation products as well as transition metal impurities. To obtain a pharmaceutical grade product, it needs to be recrystallized several times, or converted to a salt and then to a base after purification of the salt. Particular difficulty is the removal of metal impurities as their permissible concentration in the final product is in millions of parts. In turn, 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. that is well soluble in water and is difficult to separate from iron salts. In this case, in order to obtain lenalidomide in the base form, it is necessary to neutralize it with a stronger base of -5- -5- EN 14985 hydrochloride, but this process is hampered by the high amount of iron hydroxide that occurs during neutralization. All these additional procedures for cleaning the product reduce its outcome and make the technological process more expensive.

SUMMARY OF THE INVENTION

We have unexpectedly discovered that the known process of obtaining lenalidomide can be improved by new techniques for the preparation of 2- (brommethyl) -3-nitrobenzoic acid methyl ester (III) and the final product.

The methyl 2- (bromomethyl) -3-nitrobenzoic acid (III) can be obtained from the methyl ester of 2-methyl-3-nitrobenzoic acid (II) using a halogen-free solvent, methyl acetate. The open method has several advantages: the process takes place at a relatively low temperature (57 ° C), the product produces almost quantifiable output and has a high purity without further purification (98% of RES data). Given that 2- (bromomethyl) -3-nitrobenzoic acid methyl ester (III) is an indispensable raw material for the synthesis of lenalidomide, this method makes it possible to significantly reduce the use of environmentally friendly solvents in this process, to avoid the safety measures associated with the use and disposal, and to reduce the total amount of solvent. synthesis costs. Methyl acetate has practically not been studied and used as a radical bromination reaction solvent.

We also unexpectedly discovered that the final product, lenalidomide, can be obtained by reducing 3- (4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione ( IV) using ammonium chloride and iron. Surprisingly, the lenalidomide obtained in the iron and ammonium chloride system has a very low impurity content (EHH purity 98%), and it is formed in the base form, which is not possible with the metal-acid system. Advantages of the invention are low cost (iron and ammonium chloride are very inexpensive and easy to store reagents), short reaction time (4 hours) and high efficiency (product with high yield, technical product purity - 98%). Such a reduction method is not characterized by cycle opening. By simple recrystallization, it is possible to obtain a pharmaceutical purity product with a total response of -80%. -6-

EXAMPLES Example 1. Preparation of 2- (bromomethyl) -3-nitrobenzoic acid methyl ester

In a reactor equipped with a reflux condenser and a mechanical stirrer, 100.0 g (0.51 mol) of 2-methyl-3-nitrobenzoic acid methyl ester are loaded, 134.0 g (0.75 mol) of N-bromuccinimide are added and 1.0 L of methyl acetate is added. The resulting suspension is treated with 8.4 g (0.05 mol) of 2,2'-azobisisobutyronitrile and boiled for 10 18 h. (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 was filtered, evaporated, and immediately after evaporation, 90 mL of isopropanol / water (2: 1) was added to the resulting orange-yellow oil and stirred at room temperature. The product crystallizes during stirring. The precipitate 15 is filtered off and dried for 6 h. at 50-55 ° C under vacuum (10-20 mbar). Yield: 138.0 g (98%), light yellow crystals. Purity by ACE - 98%. Example 2:

Preparation of Lenalidomide Dissolve 95.6 g (1.76 mol) 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-2H-isoindol-2-yl) piperidine-2,6-dione and 2.9 L ethanol. The reaction mixture is heated to 60 ° C with 49.0 g (0.88 mol) of iron powder added under stirring. The mixture is heated at 80 ° C for 4 h. The reaction mixture was filtered hot, the precipitate was washed twice with 200 mL of hot ethanol-water solution (50 mL of water + 150 mL of ethanol). Evaporate the filtrate, add 200 mL of water to the dry residue, stir for 30 min, filter the precipitate and rinse twice with 50 mL of water. Boil the technical products for 2.5 h. with 900 mL of ethanol and 600 mL of water add 6 g of activated carbon and boil for 1 h. Filter the hot mixture. The filtrate is allowed to crystallize at -7 to -7-LV 14985 0-5 ° C, the precipitate is filtered off. The product is dried for 6 h. at 60 ° C for 15-20 mbar. Yield 47.6 g (84%) of light yellow matter. Purity by ACE -99.8%.

If necessary, the product may be recrystallized from 5 water, methanol, acetone or other solvents to give the desired polymorphic form.

Techniques are practicable in industrial production, providing an important pharmaceutical active agent for the treatment of various forms of cancer by economically advantageous and environmentally friendly methods. 10

LIST OF EQUIPMENT

Patents: 15 1. US2003 / 139451 A1,2003 2. WO2010 / 56344 A1, 2010 3. US2010 / 10060 A1,2010 4. US6335 / 349 B1, 2002 5. US5534481 A1, 1996 20 6. US6335 / 349 B1,2002 7. VV02009 / 114601 A2, 2009 8. WO2010 / 139266 A1, 2010 9. WO2010 / 56384 A1, 2010 10. WO2011 / 50962 A1, 2011 25 11. WO2011 / 27326 A1, 2011 12. WO2011 / 69608 A1, 2011 13 US2011 / 237802 A1, 2011 14. US2011 / 223157 A1, 2011 15. US2012 / 71509 A1,2012 30 16. WO2010 / 100476A2, 2010 17. WO2011 / 27326A1,2011 18. WO2011 / 111053A1, 2011 19. US2012 / 71509A1 , 2012 20. WO2010 / 61209 A1, 2010 35 Other literature: 21. Bioorg. Med. Chem. Leti., 14, 81 (2004). 22. Bioorg. Med. Chem. Leti., 9,1625 (1999). 40 23. Bioorg. Med. Chem. Leti., 3,1019 (2011).

Claims (3)

  1. -8- CLAIMS Process for the preparation of 1,3- (4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione (lenalidomide) comprising 2-methyl-3- bromination of methyl ester of nitrobenzoic acid, reaction of the methyl ester of 2- (bromomethyl) -3-nitrobenzoic acid with 3-aminopiperidine-2,6-dione obtained from 3- (4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2) -yl) reduction of piperidine-2,6-dione by 3- (4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione, which is characterized by \ t Bromination of 2-methyl-3-nitrobenzoic acid methyl ester is carried out with N-bromo-succinide in methyl acetate and 3- (4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione Reduction is by iron and ammonium chloride reducing system.
  2. The process according to claim 1, wherein the methylation of the methyl ester of 2-methyl-3-nitrobenzoic acid is carried out at a boiling point of methyl acetate in the presence of 2,2'-azobisisobutyronitrile as the initiator of radical formation.
  3. The process of claim 1, wherein the solvent in the reduction step of 3- (4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione is methanol, ethanol, propanol-2, butanol-1 or water, preferably a mixture of ethanol and water.
LVP-13-152A 2013-10-14 2013-10-14 Method for production of lenalidomide LV14985B (en)

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LVP-13-152A LV14985B (en) 2013-10-14 2013-10-14 Method for production of lenalidomide
GB1522674.9A GB2535004B (en) 2013-10-14 2014-10-03 A process for the preparation of Lenalidomide
PCT/LV2014/000010 WO2015057043A1 (en) 2013-10-14 2014-10-03 A process for the preparation of lenalidomide

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ES2733813T3 (en) * 2014-08-19 2019-12-03 Synthon Bv Process to prepare a crystalline form of lenalidomide
CN109400579A (en) * 2017-08-18 2019-03-01 新发药业有限公司 A kind of Green production method of low cost 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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WO1995000509A1 (en) 1993-06-25 1995-01-05 Kumiai Chemical Industry Co., Ltd. Indazolesulfonylurea derivative, use thereof, and intermediate for production thereof
US6281230B1 (en) 1996-07-24 2001-08-28 Celgene Corporation Isoindolines, method of use, and pharmaceutical compositions
PT1423115E (en) 2001-08-06 2009-07-21 Childrens Medical Center Antiangiogenic activity of nitrogen substituted thalidomide analogs
KR20070108881A (en) * 2005-01-27 2007-11-13 교와 핫꼬 고교 가부시끼가이샤 Igf-1r inhibitor
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NZ595492A (en) 2009-03-02 2013-07-26 Generics Uk Ltd Improved Process for the Preparation of Lenalidomide
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TWI509247B (en) 2010-03-12 2015-11-21 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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GB2535004B (en) 2019-01-02
GB201522674D0 (en) 2016-02-03
GB2535004A (en) 2016-08-10

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