RU2555370C1 - Method for enanthioselective synthesis of diethyl[3-methyl-(1s)-(nitromethyl)butyl]malonate of formula i - Google Patents
Method for enanthioselective synthesis of diethyl[3-methyl-(1s)-(nitromethyl)butyl]malonate of formula i Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 21
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 title claims abstract description 14
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 title claims abstract description 14
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 title description 3
- 238000003786 synthesis reaction Methods 0.000 title description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 21
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims abstract description 20
- CZWSUVQCPWIYID-HWKANZROSA-N (e)-4-methyl-1-nitropent-1-ene Chemical compound CC(C)C\C=C\[N+]([O-])=O CZWSUVQCPWIYID-HWKANZROSA-N 0.000 claims abstract description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- SJBYIGXWWGSEES-PMACEKPBSA-N (1s,2s)-1-n,2-n-dibenzylcyclohexane-1,2-diamine Chemical compound N([C@H]1CCCC[C@@H]1NCC=1C=CC=CC=1)CC1=CC=CC=C1 SJBYIGXWWGSEES-PMACEKPBSA-N 0.000 claims abstract description 7
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 230000003197 catalytic effect Effects 0.000 claims description 18
- -1 nitromethyl Chemical group 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 2
- 238000011084 recovery Methods 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- 229910052759 nickel Inorganic materials 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 3
- 229960001233 pregabalin Drugs 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- NQRCAVZHOLYEBJ-ZIAGYGMSSA-N 1-[3,5-bis(trifluoromethyl)phenyl]-3-[(1r,2r)-2-(dimethylamino)cyclohexyl]thiourea Chemical compound CN(C)[C@@H]1CCCC[C@H]1NC(=S)NC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 NQRCAVZHOLYEBJ-ZIAGYGMSSA-N 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 description 1
- 208000005793 Restless legs syndrome Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- BZQRBEVTLZHKEA-UHFFFAOYSA-L magnesium;trifluoromethanesulfonate Chemical compound [Mg+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F BZQRBEVTLZHKEA-UHFFFAOYSA-L 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000022925 sleep disturbance Diseases 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Настоящее изобретение относится к области органической химии, а именно к способу получения диэтил[3-метил-(1S)-(нитрометил)бутил]малоната.The present invention relates to the field of organic chemistry, and in particular to a method for producing diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate.
Диэтил[3-метил-(1S)-(нитрометил)бутил]малонат представляет собой синтетический предшественник (S)-прегабалина - препарата, используемого в терапии ряда нейропатических заболеваний и расстройств, в том числе невропатических болей, эпилепсии, фибромиалгии, мигрени, синдрома беспокойных ног, нарушений сна и др. (Pat. WO 2006/110783 A2. Process for making (S)-pregabalin (дата публикации 19.10.2006)).Diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate is a synthetic precursor of (S) -pregabalin - a drug used in the treatment of a number of neuropathic diseases and disorders, including neuropathic pain, epilepsy, fibromyalgia, migraine, syndrome restless legs, sleep disturbances, etc. (Pat. WO 2006/110783 A2. Process for making (S) -pregabalin (published date 10/19/2006)).
Данным изобретением решена задача энантиоселективного синтеза диэтил[3-метил-(1S)-(нитрометил)бутил]малоната с использованием легкодоступной и дешевой каталитической системы, используемой в виде раствора, что исключает необходимость стадии выделения каталитического комплекса в виде индивидуального соединения и обеспечивает значительное удешевление и упрощение технологического процесса.This invention solves the problem of enantioselective synthesis of diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate using an readily available and cheap catalytic system used in the form of a solution, which eliminates the need for a stage of separation of the catalytic complex as an individual compound and provides significant cost reduction and simplification of the process.
Известен ряд способов получения диэтил[3-метил-(1S)-(нитрометил)бутил]малоната, основанных на использовании органокатализаторов (Hoashy Y., Okino Т., Takemoto Y. J. Am. Chem. Soc. 2003, Vol.125, N 42, P.12672-12673; Furukawa Т., Hoashy Y., Okino Т., Takemoto Y., Xu X. J. Am. Chem. Soc. 2005, Vol.127, N 1, P.119-125; Liu J.-M., Wang X., Ge Z.-M., Sun Q., Cheng J.-M., Li R.-T. Tetrahedron. 2011, Vol.67, N 3, P.636-640). Общим недостатком этих способов является сложность строения органокатализаторов, их малодоступность и высокая стоимость, а также высокий расход органокатализаторов, требуемый для достижения каталитического эффекта.A number of methods are known for producing diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate based on the use of organocatalysts (Hoashy Y., Okino T., Takemoto YJ Am. Chem. Soc. 2003, Vol.125, N 42 , P.12672-12673; Furukawa T., Hoashy Y., Okino T., Takemoto Y., Xu XJ Am. Chem. Soc. 2005, Vol.127, N 1, P.119-125; Liu J.- M., Wang X., Ge Z.-M., Sun Q., Cheng J.-M., Li R.-T. Tetrahedron. 2011, Vol. 67, No. 3, P.636-640). A common disadvantage of these methods is the complexity of the structure of organocatalysts, their inaccessibility and high cost, as well as the high consumption of organocatalysts required to achieve a catalytic effect.
Диэтил[3-метил-(1R)-(нитрометил)бутил]малонат был получен из диэтилмалоната и 4-метил-1-нитропент-1-ена в присутствии 5.5% хирального бис-оксазолина, 5% трифлата магния, 6 мол. % N-метилморфолина и молекулярных сит (Bames D.M., Ji J., Fickes M.G. et al. J. Am. Chem. Soc. 2002. Vol.124. N 44. P.13097) с выходом 88% и энантиомерным избытком 90%.Diethyl [3-methyl- (1R) - (nitromethyl) butyl] malonate was obtained from diethyl malonate and 4-methyl-1-nitropent-1-ene in the presence of 5.5% chiral bis-oxazoline, 5% magnesium triflate, 6 mol. % N-methylmorpholine and molecular sieves (Bames DM, Ji J., Fickes MG et al. J. Am. Chem. Soc. 2002. Vol.124. N 44. P.13097) with a yield of 88% and an enantiomeric excess of 90% .
(R)-Изомер диэтил[3-метил-1-(нитрометил)бутил]малоната был получен с выходом 94% и энантиомерным избытком 88% взаимодействием двукратного избытка диэтилмалоната с 4-метил-1-нитропент-1-еном в присутствии 2 мол. % дибромобис[(R,R)-N,N′-дибензилциклогексан-1,2-диамин]никеля(II) (Evans D.A., Mito S., Seidel D. J. Am. Chem. Soc. 2007. Vol.129. N 37. P.11583).The (R) -isomer of diethyl [3-methyl-1- (nitromethyl) butyl] malonate was obtained with a yield of 94% and an enantiomeric excess of 88% by the interaction of a double excess of diethyl malonate with 4-methyl-1-nitropent-1-ene in the presence of 2 mol . % dibromobis [(R, R) -N, N′-dibenzylcyclohexane-1,2-diamine] nickel (II) (Evans DA, Mito S., Seidel DJ Am. Chem. Soc. 2007. Vol.129. N 37 P.11583).
В обоих случаях получают (R)-изомер диэтил [3-метил-1-(нитрометил)бутил]малоната, в то время как для синтеза фармацевтически активной субстанции прегабалина требуется (S)-изомер. Кроме того, большой расход хиральных лигандов (от 2 до 6 мол. %) и необходимость дополнительных стадий получения и выделения комплекса никеля(II) (Evans D.A., Mito S., Seidel D. J. Am. Chem. Soc. 2007. Vol.129. N 37. P.11583) делают данные способы малопригодными для технологической реализации.In both cases, the (R) -isomer of diethyl [3-methyl-1- (nitromethyl) butyl] malonate is obtained, while the synthesis of the pharmaceutically active substance pregabalin requires the (S) -isomer. In addition, the high consumption of chiral ligands (from 2 to 6 mol%) and the need for additional steps for the preparation and isolation of the nickel (II) complex (Evans DA, Mito S., Seidel DJ Am. Chem. Soc. 2007. Vol.129. N 37. P.11583) make these methods unsuitable for technological implementation.
Наиболее близким по технической сущности к заявляемому способу является способ получения диэтил[3-метил-(1S)-(нитрометил)бутил]малоната из 4-метил-1-нитропент-1-ена и диэтилмалоната в присутствии органокатализатора, описанный в Pat. ЕР 1640361 (A2) Asymmetric urea compound and process for producing asymmetric compound by asymmetric conjugate addition reaction with the same as catalyst (дата публикации 29.03.2006).The closest in technical essence to the claimed method is a method for producing diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate from 4-methyl-1-nitropent-1-ene and diethyl malonate in the presence of an organocatalyst described in Pat. EP 1640361 (A2) Asymmetric urea compound and process for producing asymmetric compound by asymmetric conjugate addition reaction with the same as catalyst (published date March 29, 2006).
Описанный в Pat. ЕР 1640361 (A2) способ получения диэтил[3-метил-(1S)-(нитрометил)бутил]малоната заключается в том, что к раствору нитроалкена (0.20 ммоль) и диэтилмалоната (0.40 ммоль) в толуоле добавляют в качестве катализатора (R,R)-транс-1-[3,5-бис(трифторметил)фенил]-3-[2-(N,N-диметиламино)циклогексил]тиомочевину (0.02 ммоль) при комнатной температуре в атмосфере аргона. Через 48 ч реакционную смесь концентрируют в вакууме. Продукт реакции выделяют колоночной хроматографией с использованием элюента гексан-диэтиловый эфир. Целевой продукт выделяют с выходом 88% и энантиомерным избытком (S)-изомера 81%.Described in Pat. EP 1640361 (A2) a method for the production of diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate consists in adding to the solution of nitroalkene (0.20 mmol) and diethyl malonate (0.40 mmol) as a catalyst (R, R) -trans-1- [3,5-bis (trifluoromethyl) phenyl] -3- [2- (N, N-dimethylamino) cyclohexyl] thiourea (0.02 mmol) at room temperature under argon atmosphere. After 48 hours, the reaction mixture was concentrated in vacuo. The reaction product is isolated by column chromatography using eluent hexane-diethyl ether. The expected product is isolated in 88% yield and an enantiomeric excess of the (S) -isomer 81%.
Указанный способ обладает целым рядом существенных недостатков:The specified method has a number of significant disadvantages:
1. Низкая энантиомерная чистота продукта реакции (81%).1. Low enantiomeric purity of the reaction product (81%).
2. Необходимость использования больших количеств дорогостоящего органокатализатора (10 мол. % по отношению к нитроалкену).2. The need to use large quantities of expensive organocatalyst (10 mol.% In relation to nitroalkene).
3. Необходимость использования большого количества растворителя (толуол).3. The need to use a large amount of solvent (toluene).
4. Необходимость выделения продукта реакции методом колоночной хроматографии.4. The need for isolation of the reaction product by column chromatography.
Технический результат - экономически выгодный и безопасный процесс получения диэтил[3-метил-(1S)-(нитрометил)бутил]малоната с энантиомерным избытком 96.6-97.2%, с использованием легко доступной и дешевой каталитической системы, генерируемой из гексагидрата хлорида никеля(II), (S,S)-N,N′-дибензилциклогексан-1,2-диамина и триэтиламина.EFFECT: economical and safe process for producing diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate with an enantiomeric excess of 96.6-97.2%, using an easily accessible and cheap catalytic system generated from nickel (II) chloride hexahydrate , (S, S) -N, N′-dibenzylcyclohexane-1,2-diamine and triethylamine.
Технический результат достигается тем, что диэтил[3-метил-(1S)-(нитрометил)бутил]малонат формулы IThe technical result is achieved by the fact that diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate of the formula I
получают путем энантиоселективного присоединения диэтилмалоната к 4-метил-1-нитропент-1-ену в соответствии со схемой 1obtained by enantioselective addition of diethyl malonate to 4-methyl-1-nitropent-1-ene in accordance with scheme 1
реакцию ведут при добавлении каталитической системы, представляющей собой раствор гексагидрата хлорида никеля, (S,S)-N,N′-дибензилциклогексан-1,2-диамина и триэтиламина в мольном соотношении 1:1:1 в метаноле, расход хирального лиганда может быть снижен до 0.05 мол. % по отношению к 4-метил-1-нитропент-1-ену.the reaction is carried out by adding a catalytic system, which is a solution of nickel chloride hexahydrate, (S, S) -N, N′-dibenzylcyclohexane-1,2-diamine and triethylamine in a 1: 1: 1 molar ratio in methanol, the chiral ligand consumption can be reduced to 0.05 mol. % in relation to 4-methyl-1-nitropent-1-ene.
Отличительные признаки:Features:
1. Проведение реакции диэтилмалоната с 4-метил-1-нитропент-1-еном в присутствии каталитической системы, представляющей собой раствор гексагидрата хлорида никеля, (S,S)-N,N′-дибензилциклогексан-1,2-диамина и триэтиламина в мольном соотношении 1:1:1 в метаноле.1. The reaction of diethyl malonate with 4-methyl-1-nitropent-1-ene in the presence of a catalytic system that is a solution of nickel chloride hexahydrate, (S, S) -N, N′-dibenzylcyclohexane-1,2-diamine and triethylamine 1: 1: 1 molar ratio in methanol.
2. Компоненты каталитической системы используются в соотношении 0.05-1 мол. % по отношению к 4-метил-1-нитропент-1-ену.2. The components of the catalytic system are used in a ratio of 0.05-1 mol. % in relation to 4-methyl-1-nitropent-1-ene.
Заявляемое изобретение имеет следующие преимущества:The claimed invention has the following advantages:
Удешевление производства за счет применения в качестве каталитической системы энантиоселективного присоединения диэтилмалоната к 4-метил-1-нитропент-1-ену раствора компонентов каталитической системы в низкой концентрации (0.05-1 мол. %) и отказа от использования дорогостоящих органокатализаторов - производных тиомочевины.Cheaper production due to the use of enantioselective addition of diethyl malonate to 4-methyl-1-nitropent-1-ene as a catalytic system, a solution of the components of the catalytic system in low concentration (0.05-1 mol%) and the rejection of the use of expensive organocatalysts - derivatives of thiourea.
Упрощение технологического процесса за счет использования каталитической системы в виде раствора (без дополнительных стадий выделения индивидуального комплекса) и отсутствия необходимости хроматографического выделения продукта реакции.The simplification of the process due to the use of a catalytic system in the form of a solution (without additional stages of separation of an individual complex) and the absence of the need for chromatographic isolation of the reaction product.
Обеспечение экологической безопасности процесса за счет отказа от использования больших количеств растворителей.Ensuring environmental safety of the process due to the rejection of the use of large quantities of solvents.
Примеры выполнения способаExamples of the method
Спектры ЯМР регистрировали на приборе Jeol JNM-ECX400 с использованием растворителя CDCl3 [399.78 (1H) и 100.53 МГц (13C)]. Измерения проводили без использования дополнительных эталонов с привязкой частоты к сигналу дейтерированного растворителя.NMR spectra were recorded on a Jeol JNM-ECX400 instrument using CDCl 3 solvent [399.78 ( 1 H) and 100.53 MHz ( 13 C)]. The measurements were carried out without the use of additional standards with reference to the frequency of the signal of the deuterated solvent.
Масс-спектры получены на хромато-масс-спектрометре Finnigan Trace DCQ с использованием капиллярной колонки ВРХ-5 30×0.32 компании SGE при энергии ионизирующих электронов 70 эВ.Mass spectra were obtained on a Finnigan Trace DCQ gas chromatography mass spectrometer using a SGE capillary column BPX-5 30 × 0.32 at an ionizing electron energy of 70 eV.
Энантиомерный состав продукта реакции определен методом ВЭЖХ на жидкостном хроматографе Waters, оснащенном спектрофотометрическим детектором Waters 2487 и рефрактометрическим детектором Waters 2414. Условия анализа для диэтил[(2S)-4-метил-1-нитропент-2-ил]малоната: колонна Chiralcel AD; мобильная фаза : гексан : изопропанол (95:5), расход 1.0 мл/мин.The enantiomeric composition of the reaction product was determined by HPLC on a Waters liquid chromatograph equipped with a Waters 2487 spectrophotometric detector and a Waters 2414 refractometric detector. Analysis conditions for diethyl [(2S) -4-methyl-1-nitropent-2-yl] malonate: Chiralcel AD column; mobile phase: hexane: isopropanol (95: 5), flow rate 1.0 ml / min.
Для катализа реакции 4-метил-1-нитропент-1-ена с диэтилмалонатом использовался 0.1 М раствор каждого из компонентов каталитической системы в метаноле.A 0.1 M solution of each of the components of the catalytic system in methanol was used to catalyze the reaction of 4-methyl-1-nitropent-1-ene with diethyl malonate.
Пример 1Example 1
Получение каталитической системыCatalytic System Preparation
К 740 мг (2.52 ммоль) (S,S)-N,N′-дибензилциклогексан-1,2-диамина и 598 мг (2.52 ммоль) гексагидрата хлорида никеля(II) добавляли 25.2 мл метанола и перемешивали до полного растворения реагентов; затем к полученному раствору добавляли 0.350 мл (255 мг, 2.52 ммоль) триэтиламина. Полученный раствор использовали в реакции.To 740 mg (2.52 mmol) of (S, S) -N, N′-dibenzylcyclohexane-1,2-diamine and 598 mg (2.52 mmol) of nickel (II) chloride hexahydrate, 25.2 ml of methanol was added and stirred until the reagents were completely dissolved; then, 0.350 ml (255 mg, 2.52 mmol) of triethylamine was added to the resulting solution. The resulting solution was used in the reaction.
Диэтил [3-метил-(1S)-(нитрометил)бутил] малонатDiethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate
Пример 2Example 2
К 12.1 г (93.5 ммоль) 4-метил-1-нитропент-1-ена и 30.0 г (187 ммоль) диэтилмалоната добавляли 9.35 мл каталитического раствора (0.935 ммоль, 1 мол. % Ni), полученного по методике, описанной в Примере 1. Реакционную массу выдерживали при температуре 50°C в течение 5 ч. Избыток диэтилмалоната отгоняли в вакууме при остаточном давлении 20 мм рт.ст. Выход: 27.1 г (количественный). ЯМР 1H (CDCl3), δ, м.д.: 0.85-0.87 м. (6Н), 1.20-1.29 м (8Н), 1.57-1.63 м (1Н), 2.87-2.92 м (1Н), 3.55 д (1Н, JHH 5.6 Гц), 4.13-4.19 м (4Н), 4.46 дд (1Н, JHH 13.2, 6.4 Гц), 4.65 дц (1Н, JHH 13.2, 4.8 Гц). δC, м.д.: 13.8, 13.9, 22.1, 22.2, 25.0, 34.7, 38.9, 52.6, 61.6, 61.7, 76.8, 167.7, 167.9. ГХ-MC, m/z (Iотн, %): 243 (6, M+ - NO2), 215 (10), 169 (25), 160 (100), 133 (30), 55 (35). ВЭЖХ: время выхода (R)-изомера 6.4 мин, (S)-изомера 8.8 мин. По данным ВЭЖХ энантиомерный избыток (S)-изомера 97.2%.To 12.1 g (93.5 mmol) of 4-methyl-1-nitropent-1-ene and 30.0 g (187 mmol) of diethyl malonate was added 9.35 ml of a catalytic solution (0.935 mmol, 1 mol% Ni) obtained by the procedure described in Example 1 The reaction mass was kept at a temperature of 50 ° C for 5 hours. The excess diethyl malonate was distilled off in vacuo at a residual pressure of 20 mm Hg. Yield: 27.1 g (quantitative). NMR 1 H (CDCl 3 ), δ, ppm: 0.85-0.87 m. (6Н), 1.20-1.29 m (8Н), 1.57-1.63 m (1Н), 2.87-2.92 m (1Н), 3.55 d (1H, J HH 5.6 Hz), 4.13-4.19 m (4H), 4.46 dd (1H, J HH 13.2, 6.4 Hz), 4.65 dts (1H, J HH 13.2, 4.8 Hz). δ C , ppm: 13.8, 13.9, 22.1, 22.2, 25.0, 34.7, 38.9, 52.6, 61.6, 61.7, 76.8, 167.7, 167.9. GC-MS, m / z (I Rel ,%): 243 (6, M + - NO 2 ), 215 (10), 169 (25), 160 (100), 133 (30), 55 (35). HPLC: exit time of the (R) -isomer 6.4 min, (S) -isomer 8.8 min. According to HPLC, the enantiomeric excess of the (S) -isomer is 97.2%.
Пример 3Example 3
К 12.1 г (93.5 ммоль) 4-метил-1-нитропент-1-ена и 30.0 г (187 ммоль) диэтилмалоната добавляли 1.87 мл каталитического раствора (0.187 ммоль, 0.2 мол. % Ni), полученного по методике, описанной в Примере 1. Реакционную массу выдерживали при температуре 50°C в течение 15 ч. Избыток диэтилмалоната отгоняли в вакууме при остаточном давлении 20 мм рт.ст. Выход: 27.1 г (количественный). Энантиомерный избыток (S)-изомера 96.8%.To 12.1 g (93.5 mmol) of 4-methyl-1-nitropent-1-ene and 30.0 g (187 mmol) of diethyl malonate was added 1.87 ml of a catalytic solution (0.187 mmol, 0.2 mol% Ni) obtained by the procedure described in Example 1 The reaction mass was kept at a temperature of 50 ° C for 15 hours. The excess diethyl malonate was distilled off in vacuo at a residual pressure of 20 mm Hg. Yield: 27.1 g (quantitative). Enantiomeric excess of (S) -isomer 96.8%.
Пример 4Example 4
К 25.7 г (199 ммоль) 4-метил-1-нитропент-1-ена и 63.7 г (398 ммоль) диэтилмалоната добавляли 1.00 мл каталитического раствора (0.100 ммоль, 0.05 мол. % Ni), полученного по методике, описанной в Примере 1. Реакционную массу выдерживали при температуре 50°C в течение 15 ч. Избыток диэтилмалоната отгоняли в вакууме при остаточном давлении 20 мм рт.ст. Выход: 57.6 г (количественный). Энантиомерный избыток (S)-изомера 96.6%.To 25.7 g (199 mmol) of 4-methyl-1-nitropent-1-ene and 63.7 g (398 mmol) of diethyl malonate were added 1.00 ml of a catalytic solution (0.100 mmol, 0.05 mol% Ni) obtained by the procedure described in Example 1 The reaction mass was kept at a temperature of 50 ° C for 15 hours. The excess diethyl malonate was distilled off in vacuo at a residual pressure of 20 mm Hg. Yield: 57.6 g (quantitative). Enantiomeric excess of (S) -isomer 96.6%.
Пример 5Example 5
К 258 г (2.00 моль) 4-метил-1-нитропент-1-ена и 641 г (4.00 ммоль) диэтилмалоната добавляли 10 мл каталитического раствора (1 ммоль, 0.05 мол. % Ni), полученного по методике, описанной в Примере 1. Реакционную массу выдерживали при температуре 50°C в течение 15 ч. Избыток диэтилмалоната отгоняли в вакууме при остаточном давлении 20 мм рт.ст. Выход: 579 г (количественный). Энантиомерный избыток (S)-изомера 96.6%.To 258 g (2.00 mol) of 4-methyl-1-nitropent-1-ene and 641 g (4.00 mmol) of diethyl malonate were added 10 ml of a catalytic solution (1 mmol, 0.05 mol% Ni) obtained by the procedure described in Example 1 The reaction mass was kept at a temperature of 50 ° C for 15 hours. The excess diethyl malonate was distilled off in vacuo at a residual pressure of 20 mm Hg. Yield: 579 g (quantitative). Enantiomeric excess of (S) -isomer 96.6%.
Claims (2)
путем энантиоселективного присоединения диэтилмалоната к 4-метил-1-нитропент-1-ену в соответствии со схемой
отличающийся тем, что реакцию диэтилмалоната с 4-метил-1-нитропент-1-еном ведут в присутствии каталитической системы, представляющей собой раствор гексагидрата хлорида никеля, (S,S)-N,N′-дибензилциклогексан-1,2-диамина и триэтиламина в мольном соотношении 1:1:1 в метаноле.1. The method of obtaining diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate of the formula I
by enantioselective addition of diethyl malonate to 4-methyl-1-nitropent-1-ene according to the scheme
characterized in that the reaction of diethyl malonate with 4-methyl-1-nitropent-1-ene is carried out in the presence of a catalytic system that is a solution of nickel chloride hexahydrate, (S, S) -N, N′-dibenzylcyclohexane-1,2-diamine and triethylamine in a molar ratio of 1: 1: 1 in methanol.
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