WO2019239341A1 - Process for asymmetric synthesis of (r)-4-propyldihydrofuran-2 (3h)-one - Google Patents
Process for asymmetric synthesis of (r)-4-propyldihydrofuran-2 (3h)-one Download PDFInfo
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- WO2019239341A1 WO2019239341A1 PCT/IB2019/054907 IB2019054907W WO2019239341A1 WO 2019239341 A1 WO2019239341 A1 WO 2019239341A1 IB 2019054907 W IB2019054907 W IB 2019054907W WO 2019239341 A1 WO2019239341 A1 WO 2019239341A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/50—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
- C07C205/51—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/16—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
Definitions
- the invention relates to a process for the asymmetric synthesis of (R)- 4- propyldihydrofuran-2(3H)-one, the intermediate used for the synthesis of the active ingredient Brivaracetam.
- Brivaracetam is the n-propyl derivative of levetiracetam; the presence of the aliphatic chain gives it greater hydrophobic properties, which are responsible for a more rapid passage through the blood-brain barrier, and consequently a more efficient pharmacological action on the nervous system than its predecessor.
- Brivaracetam is currently considered to be one of the most promising third-generation antiepileptics.
- the desired stereocentre is present in the starting raw material, ( ? -3-methoxycarbonyl hexanoic acid.
- CN 107698543 A discloses a procedure starting with L-glyceric acid.
- WO2018042393A1 discloses a procedure that uses chiral auxiliaries.
- A* chiral auxiliary
- US8957226 discloses a double separation on chiral stationary phase: the first separation relates to the two enantiomers of the lactam intermediate, and the second to the two diastereoisomers of the final mixture.
- composition of the final mixture reported in the text, actually consists of all four of the possible diastereoisomers of the end product (44.34%, 40.49%, 7.73% and 7.44%).
- the stereocentre with R absolute configuration is generated by a catalysis method that uses as catalysts small organic molecules, which are cheap and easily recoverable (and therefore reusable), and devoid of transition metals, so that there is no need to test the end product for traces of said metals.
- the process comprises the following steps:
- Ci-C 4 alkyl indicates the radical of a straight or branched alkyl chain having 1 to 4 carbon atoms, such as methyl, ethyl, propyl or butyl.
- Examples of“Ci-C 4 alkoxy” groups include the methoxy, ethoxy, propoxy and butoxy groups.
- Steps b), c) and d) proceed without alteration of the R : S enantiomeric ratio resulting from step a).
- Salification offers the possibility of isolating a crystalline solid with a chemical purity exceeding 99%, therefore limiting all the impurities deriving from steps a) and b).
- a further object of the invention is therefore compounds of Formula (I)
- R is selected from hydrogen and straight or branched C1-C4 alkyl.
- the preferred compounds of formula (I) are ( ?j-3-(nitromethyl)hexanoic acid and methyl (7?)-3-(nitromethyl)hexanoate.
- a further object of the invention is therefore compounds of formula (II)
- a + is the protonated form of a base selected from /3 ⁇ 4)-(-)- 1- phenylethylamine, (7?)-(-)-l -phenylethylamine, quinine, quinidine, cinchonine, cinchonidine, triethylamine, diethylamine, methylamine, ammonia, diisopropylethylamine, dicyclohexylamine, benzylamine, morpholine, guanidine, pyrrolidine, l ,8-diazabicyclo[5.4.0]undec-7-ene, l ,4-diazabicyclo[2.2.2]octane, 1 ,5,7- triazabiciclo[4.4.0]dec-5-ene, ($)-(+)- l-cyclohexylethylamine and (R)-(-)- ⁇ - cyclohexylethylamine.
- a further object of the invention is the use of a compound of Formula (I) or a compound of Formula (II) as defined above to prepare Brivaracetam.
- the process is conducted as follows:
- a catalyst selected from 5 , )-(-)-a,a-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether, /. /-( ⁇ )-a,a-diphenyl-2-pyrrolidinemethanol / ⁇ ?
- 1-5 moles of monobasic potassium phosphate, preferably 2-3 moles, and 1 -5 moles of sodium chlorite (25% w/w aqueous solution), preferably 2-3 moles, are added to the mixture at a temperature ranging from -10 to +20°C, preferably from -5 to +10°C.
- Step b2) 1 mole of ( ?)-3-(nitromethyl)hexanal is dissolved in 5-50 volumes, preferably 10-20 volumes, of a solvent selected from methanol, ethanol, isopropanol, 77- propanol and /er/-butanol, preferably methanol, and 1-3 moles of N-bromosuccinimide, preferably 1.3-1.7 moles, are added at a temperature ranging from -5 to +10°C, preferably from 0 to +5°C.
- 1 mole of acid is dissolved in 1-20 volumes, preferably 2-10 volumes, of a solvent selected from methanol, ethanol, isopropanol, «-propanol, ethyl acetate, isopropyl acetate, dichloromethane and toluene, preferably methanol, at a temperature ranging from 10 to 50°C, preferably from 20 to 40°C.
- a solvent selected from methanol, ethanol, isopropanol, «-propanol, ethyl acetate, isopropyl acetate, dichloromethane and toluene, preferably methanol
- a base suitably selected from (S)-(-)- 1- phenylethylamine, (/?)-(-)- l -phenylethylamine, quinine, quinidine, cinchonine, cinchonidine, triethylamine, diethylamine, methylamine, ammonia, diisopropylethylamine, dicyclohexylamine, benzylamine, morpholine, guanidine, pyrrolidine, l ,8-diazabicyclo[5.4.0]undec-7-ene, l ,4-diazabicyclo[2.2.2]octane, 1 ,5,7- triazabiciclo[4.4.0]dec-5-ene and (S)-(+)- l-cyclohexylethylamine, (7?)-(-)-l- .
- cyclohexylethylamine preferably ( 3 ⁇ 4)-(-)- 1 -phenylethylamine 0.8-1. moles, preferably 0.9- 1.2 moles, is added to the solution, and 1-20 volumes, preferably 2-10 volumes, of a solvent suitably selected from diisopropyl ether, cyclopentyl methyl ether and methyl- /e/7-butyl ether, preferably diisopropyl ether, are dripped in.
- a solvent suitably selected from diisopropyl ether, cyclopentyl methyl ether and methyl- /e/7-butyl ether, preferably diisopropyl ether
- the salt is released by suspending 1 mole thereof in 1-20 volumes, preferably 2-10 volumes, of a solvent selected from methyl-/er/-butyl ether, diisopropyl ether and cyclopentyl methyl ether, preferably methyl-/cr/-butyl ether, to which a dilute aqueous solution of HC1 is added such that the quantity of HC1 is from 1 to 3 moles, preferably from 1.1 to 1.5 moles.
- a solvent selected from methyl-/er/-butyl ether, diisopropyl ether and cyclopentyl methyl ether, preferably methyl-/cr/-butyl ether
- 0.001-0.01 moles of concentrated sulphuric acid preferably 0.003-0.006 moles, is added at a temperature ranging from +20 to +60°C, preferably from +30 to +50°C, to 1 mole of the product (7? /) -3-(nitromethyl)hexanoic acid (in the enantiomeric ratio R : S > 99.5 : 0.5), dissolved in a solvent selected from methanol, ethanol, isopropanol, n- propanol and /c;7-butanol, preferably methanol.
- the product methyl (R)-3- (nitromethyl)hexanoate is obtained in the enantiomeric ratio R : S > 99.5 : 0.5.
- a solvent selected from dimethylsulphoxide, N,N- dimethylacetamide and N,N-dimethylformamide, preferably dimethylsulphoxide
- a solvent selected from tetrahydrofuran, methylte
- the progress of the reaction is monitored by 'H-NMR analysis. After filtration of the resulting suspension, at a temperature ranging from -10 to +l0°C, preferably from -5 to +5°C, 1-5 moles, preferably 1.2-3.5 moles, of sodium borohydride are added, followed by the addition of 1-20 moles, preferably 2-10 moles, of methanol. The progress of the reaction is monitored by 'H-NMR analysis.
- the reaction mixture containing the non-isolated intermediate methyl (R)- 3- (hydroxymethyl)hexanoate is concentrated, diluted with a solvent selected from dichloromethane, tetrahydrofuran, methyltetrahydrofuran, toluene, isopropyl acetate and ethyl acetate, preferably dichloromethane, and treated with 0.1 -0.5 moles of an acid selected from -toluenesulphonic, trifluoroacetic, hydrochloric, sulphuric, formic, acetic and citric acid, preferably -toluenesulphonic acid, at a temperature ranging from -20 to +40°C, preferably from -5 to 25°C.
- a solvent selected from dichloromethane, tetrahydrofuran, methyltetrahydrofuran, toluene, isopropyl acetate and ethyl acetate, preferably dichloromethane,
- the enantiomeric ratio of the product ( R : S > 99.5 : 0.5) is monitored by chiral stationary phase liquid chromatography.
- the enantiomeric ratio of the product ( R : S > 99.5 : 0.5) is monitored by chiral stationary phase liquid chromatography.
- the resulting suspension is filtered to remove the morpholinium salts, and 4.3 g of sodium borohydride (1 14.8 mmols) is added in portions to the filtrate at 0°C, followed by 5 mL of MeOH, dripped in at the same temperature in 30 minutes.
- 30 mL of a 2N HC1 aqueous solution is added, and the mixture is stirred at 20°C for 30 minutes, before concentrating the organic solvents at low pressure and adding 50 mL of dichloromethane.
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Abstract
The invention relates to a process for the asymmetric synthesis of (R)-4-propyldihydrofuran-2(3H)-one starting with trans-2-hexen-l-al and nitromethane, wherein the stereocentre is generated for the first time by an organocatalytic method, which is therefore highly economical and industrially scalable, and has a very low environmental impact (Formula I).
Description
PROCESS FOR ASYMMETRIC SYNTHESIS OF (R)- 4-
PROPYLDIHYDROFURAN-2 -ONE
Field of invention
The invention relates to a process for the asymmetric synthesis of (R)- 4- propyldihydrofuran-2(3H)-one, the intermediate used for the synthesis of the active ingredient Brivaracetam.
Background to the invention
(7? -4-Propyldihydrofuran-2(3H)-one is the key intermediate in the diastereoselective synthesis of Brivaracetam, an active ingredient with antiepileptic properties belonging to the racetam family.
BRIVARACETAM
iS)-2-((2?l-2-oxo-4-propylpyrrolidin- 1 -yl)butanamide Brivaracetam is the n-propyl derivative of levetiracetam; the presence of the aliphatic chain gives it greater hydrophobic properties, which are responsible for a more rapid passage through the blood-brain barrier, and consequently a more efficient pharmacological action on the nervous system than its predecessor.
Moreover, Phase III clinical trials have demonstrated that the most common side effects attributed to this category of drugs (irritability, depression and outbursts of anger) have considerably reduced from levetiracetam (10% of patients) to Brivaracetam (2% of patients).
For both reasons, Brivaracetam is currently considered to be one of the most promising third-generation antiepileptics.
In terms of synthesis, control of the ( R ) stereochemistry of the 4-n-propyl group is unanimously considered to be the greatest difficulty, whereas the stereochemistry of the
(25) stereocentre can easily be controlled by using (5)-2-aminobutanamide, which is cheap and widely available, as building block.
As a consequence, syntheses of Brivaracetam using as key precursor (¾)-4-propyldihydrofuran-2(3H)-one, a compound with the absolute configuration of the stereocentre already defined, are undoubtedly the most innovative, as they do not require expensive investments in chromatographic equipment designed to separate the final diastereoisomeric mixture, consisting of Brivaracetam and the diastereoisomer thereof.
The following are examples of synthesis of (7?)-4-propyldihydrofuran-2(3H)-one, sometimes expressly used as key intennediate to obtain Brivaracetam:
- WO2016191435A1, wherein the stereocentre with the R configuration is already present in the starting raw material, (7?)-epichlorohydrin.
(7?/-epichlorohydrin
BRIVARACETAM p? -4-propyldihydrofuran-2(3H)-one
The obvious problem with this synthesis is that ( ?)-epichlorohydrin is a known carcinogen, as well as being extremely expensive in its enantiopure form. This naturally gives rise to serious doubts about the environmental impact of an industrial scale-up (on both workers and the environment), and considerations regarding the obligation to conduct meticulous research into genotoxic impurities, deriving from (R)- epichlorohydrin, in the finished product. Moreover, the reaction conditions in the decarboxylation step are very extreme (T>l00°C in an aqueous medium), and such conditions usually tend to affect the optical and chemical purity of the desired product.
Also in CN 106588831 A, the desired stereocentre is present in the starting raw
material, ( ? -3-methoxycarbonyl hexanoic acid.
(7?,/-3-methoxycarbonyl hexanoic acid (7?j-4-propyldihydrofuran-2(3H)-one
BRIVARACETAM
The fact that said substance is totally unavailable from industrial suppliers worldwide makes the synthesis (of the raw material and therefore of (R)- 4- propyldihydrofuran-2(3H)-one) much longer and more complex than that simplistically reported on paper, and therefore of little industrial interest.
Org. Process. Res. Dev., 2016, 20 (9), 1566 describes a method of obtaining the R stereocentre by enzymatic resolution (which already conceptually involves a maximum yield of only 50% for the single step) of the racemic mixture of methyl 2-propyIsuccinate 4-terf-butyl ester to obtain ( ? -2-propylsuccinic acid 4-/er/-butyl ester.
In practice, the synthesis takes much longer, because in order to obtain the racemic mixture of methyl 2-propylsuccinate 4- /7-butyl ester, the starting material for the key
step wherein the stereocentre is generated, another 3 steps are required, starting from dimethyl malonate, the only commercially available raw material. Moreover, as expressly reported in the text,“silica-gel column chromatography is necessary to achieve a purity acceptable for the study of enzymatic resolution”, a factor which means that this procedure is of even less industrial importance.
VieO"
dimet
methyl 2-propylsuccinate
4-fert-butyl ester
(racemic mixture)
Furthemore, the difficulties typically associated with the use of enzymes should be borne in mind, such as the difficult purification of the desired intermediates from protein material (or optionally other types of material) deriving from enzymes, as well as regulatory problems.
CN 107698543 A discloses a procedure starting with L-glyceric acid.
L-glyceric acid inversion of
stereocentre ί
(R)-4-propy\di ydrofuran-2(3H)-Qne
The evident length of the synthesis (10 steps), the poor commercial availability of
the starting raw material (which is also extremely expensive when sold in enantiopure form) and the need for total inversion of the stereocentre configuration (which is never completely achieved in nucleophilic substitution reactions) make this synthesis wholly unsuitable for industrial application.
WO2018042393A1 discloses a procedure that uses chiral auxiliaries.
A* = chiral auxiliary
X = halogen
The industrial application of said procedures is limited, because in order to generate a stereocentre with an enantiomeric ratio at least exceeding 95 : 5, a temperature ranging from -60 to -78°C is usually necessary, which would require a large investment in suitable equipment. Moreover, the procedures for removing the chiral auxiliary can sometimes adversely affect the chemical purity of the desired intermediate.
Syntheses of Brivaracetam not involving the optically active synthon (R)- 4- propyldihydrofuran-2(3H)-one cannot generate the stereocentre with absolute R configuration (bonded to the «-propyl chain); consequently, in order to separate enantiomeric mixtures (of intermediates) or diastereoisomeric mixtures (of the end product and the diastereoisomer thereof), it is necessary to use chromatographic methods with a chiral stationary phase, which in some cases prove to be industrially inapplicable, while in other cases they require huge investments to perform the industrial scale-up of the process concerned.
Moreover, the need for chromatography by definition indicates the non- quantitative formation of the desired product, leading to a significant loss of yield.
For example, US7629474 discloses a synthesis wherein expensive chromatographic separation (on chiral stationary phase) of Brivaracetam and the diastereoisomer thereof is required at the end.
undesirable BRIVARACETAM
diastereoisomer
need for chromatographic separation
US8957226 discloses a double separation on chiral stationary phase: the first separation relates to the two enantiomers of the lactam intermediate, and the second to the two diastereoisomers of the final mixture.
WWARACeTAV
This procedure is unsuitable per se for industrial scale-up or for any laboratory synthesis application, whereas it would be acceptable for a purely analytical study (involving quantities of the order of milligrams).
In US8338621, unlike the preceding case, the procedure begins with an optically active synthon, methyl (7?)-2-bromobutanoate (described by the authors as “substantially optically pure”), but chromatographic separation is still required at the end.
actually a mixture of the 4
possible diastereoiso ers
Other problems in addition to this obvious, recurrent drawback are the low availability of the optically active bromoderivative, its probable tendency to racemisation, its high cost, and the fact that to obtain the final active ingredient, the stereocentre of the raw material must be completely inverted by nucleophilic substitution which, however, never takes place completely.
This is demonstrated by the fact that the composition of the final mixture, reported in the text, actually consists of all four of the possible diastereoisomers of the end product (44.34%, 40.49%, 7.73% and 7.44%).
J Med Chem, 2004, 47, 530 also reports procedures that produce the usual mixture of Brivaracetam and the diastereoisomer thereof, and therefore require chromatographic purifications at the end.
undesirable QRIVARACETAM
diastereoisomer
need for chromatographic separation
need for chromatographic separation
II
In view of the factors described above, Brivaracetam syntheses involving the synthon with the already defined stereocentre (7? -4-propyldihydrofuran-2(3H)-one would be far more acceptable from the industrial standpoint than those requiring chromatographic purifications.
However, to date, as already stated, synthesis methods using (R)-4- propyldihydrofuran-2(3H)-one also present numerous problems, sometimes associated with the toxicity of the reagents, and sometimes with their very low availability or
exorbitant cost, or the need for processes unsuitable for industrial scale-up (use of enzymes or chiral auxiliaries).
Description of the invention
A novel process for the asymmetric synthesis of 7?)-4-propyldihydrofuran-2(3H)- one has surprisingly been found.
It is the first synthesis of said compound which is concretely suitable for industrial scale-up, does not use carcinogenic raw materials, and uses very cheap, widely available raw materials.
Moreover, for the first time, the stereocentre with R absolute configuration is generated by a catalysis method that uses as catalysts small organic molecules, which are cheap and easily recoverable (and therefore reusable), and devoid of transition metals, so that there is no need to test the end product for traces of said metals.
In view of the absence of metals in the catalyst of key step a), during which the stereocentre is generated, meticulous neutralisation of the reaction mixture is wholly superfluous.
In total contrast with the existing methods described in the literature, this process generates the desired stereocentre with almost quantitative enantiomeric enrichment, with no need to operate at low temperatures.
The process comprises the following steps:
a) asymmetric addition reaction of nitromethane to trans- 2-hexen-l-al in the presence of a catalyst selected from (5))-(-)-a,a-diphenyl-2-pyiTolidinemethanol trimethylsilyl ether (either commercially available or generated in situ from ( S)-(-)-a,a - diphenyl-2-pyrrolidinemethanol, trimethylsilyl chloride and imidazole), (S)-(-)-a,a- diphenyl-2-pyrrolidinemethanol r/-butyldimethylsilyl ether and (S)-(-)-5-(2- pyrrolidinyl)-l//-tetrazole, in the presence of weak acids at room temperature, to obtain (7?)-3-(nitromethyl)hexanal with the ratio between enantiomers R : S of 97 : 3;
b) conversion of (^-3-(nitromethyl)hexanal to a O-04 alkyl (R)- 3- (nitromethyl)hexanoate, by:
bl ) reaction of (7?,)-3-(nitromethyl)hexanal with aqueous sodium chlorite to give ( ?7-3-(nitromethyl)hexanoic acid, which is subjected to Fischer esterification in a Ci-C4 alkyl alcohol to give said Ci-C4 alkyl (R)- - (nitromethyl)hexanoate; or
b2) direct oxidation of (7?)-3-(nitromethyl)hexanal with N- bromosuccinimide in a Ci-C4 alkyl alcohol to give said Ci-C4 alkyl (R)- 3- (nitromethyl)hexanoate;
c) reaction of said Ci-C4 alkyl ( ?)-3-(nitromethyl)hexanoate in the presence of sodium nitrite and acetic acid to give an (R)-2-(2-(C\-C4 alkoxy)-2-oxoethyl) pentanoic acid;
d) cyclisation of said (7?)-2-(2-(Ci-C4 alkoxy)-2-oxoethyl)pentanoic acid to (R)- 4-propyldihydrofuran-2(3H)-one:
dl) directly, by reaction with borane-dimethylsulphide complex; or d2) after reduction to give a Ci-C4 alkyl (R)- 3-(hydroxymethyl)- hexanoate by reaction with sodium borohydride of the mixed anhydride obtained by reacting said (7? -2-(2-(Ci-C4 alkoxy)-2-oxoethyl)pentanoic acid with an alkyl chloroformate selected from ethyl chloroformate and isobutyl chloroformate in the presence of a base selected from N-methylmorpholine, triethylamine and diisopropylethylamine, said reduction being followed by acid catalysed cyclisation to give ( ? -4-propyldihydrofuran-2(3H)-one.
The term“Ci-C4 alkyl” indicates the radical of a straight or branched alkyl chain having 1 to 4 carbon atoms, such as methyl, ethyl, propyl or butyl.
Examples of“Ci-C4 alkoxy” groups include the methoxy, ethoxy, propoxy and butoxy groups.
Steps b), c) and d) proceed without alteration of the R : S enantiomeric ratio resulting from step a).
The production of ( ?,)-4-propyldihydrofuran-2(3H)-one in the R : S enantiomeric ratio of 97 : 3 provides Brivaracetam with a diastereoisomeric purity exceeding 99.80% if
the synthesis and crystallisation methods reported in the literature are followed.
However, a further improvement can be achieved when (R)- 3-
(nitromethyl)hexanoic acid is obtained in step b).
In fact, by reacting the latter with a base selected from (S)-(~)- 1- phenylethylamine, (7?)-(-)-l -phenylethylamine, quinine, quinidine, cinchonine, cinchonidine, triethylamine, diethylamine, methylamine, ammonia, diisopropylethylamine, dicyclohexylamine, benzylamine, morpholine, guanidine, pyrrolidine, l,8-diazabicyclo[5.4.0]undec-7-ene, l,4-diazabicyclo[2.2.2]octane, 1,5,7- triazabiciclo[4.4.0]dec-5-ene, ¾)-(+)- 1 -cyclohexylethylamine and (R)-(-)-\- cyclohexylethylamine, preferably (¾)-(-)- 1 -phenylethylamine, the corresponding salt is obtained in the enantiomeric ratio R : S > 99.5 : 0.5, and said ratio is maintained in the fmal(7? -4-propyldihydrofuran-2(3H)-one.
Salification offers the possibility of isolating a crystalline solid with a chemical purity exceeding 99%, therefore limiting all the impurities deriving from steps a) and b).
Obviously, starting with an (7?M-propyldihydrofuran-2(3H)-one in the enantiomeric ratio R : S > 99.5 : 0.5, a Brivaracetam with diastereoisomeric purity exceeding 99.80% is all the more likely to be obtained by following the synthesis and crystallisation methods reported in the literature.
The enantiomerically enriched intermediate /¾)-3-(nitromethyl)hexanoic acid, wherein the ratio of the R stereoisomer to the S stereoisomer is still greater than 96 : 4, and the esters thereof with a straight or branched C!-C4 alkyl alcohol obtained in step bl) of the process according to the invention, are novel.
A further object of the invention is therefore compounds of Formula (I)
wherein R is selected from hydrogen and straight or branched C1-C4 alkyl.
The preferred compounds of formula (I) are ( ?j-3-(nitromethyl)hexanoic acid and
methyl (7?)-3-(nitromethyl)hexanoate.
The enantiomerically enriched salts of ( ?/)-3-(nitromethyl)hexanoic acid with a base, wherein the ratio of the R stereoisomer to the S stereoisomer of the acid is still greater than 96 : 4, are novel.
A further object of the invention is therefore compounds of formula (II)
wherein A+ is the protonated form of a base selected from /¾)-(-)- 1- phenylethylamine, (7?)-(-)-l -phenylethylamine, quinine, quinidine, cinchonine, cinchonidine, triethylamine, diethylamine, methylamine, ammonia, diisopropylethylamine, dicyclohexylamine, benzylamine, morpholine, guanidine, pyrrolidine, l ,8-diazabicyclo[5.4.0]undec-7-ene, l ,4-diazabicyclo[2.2.2]octane, 1 ,5,7- triazabiciclo[4.4.0]dec-5-ene, ($)-(+)- l-cyclohexylethylamine and (R)-(-)-\- cyclohexylethylamine.
The preferred compounds of formula (II) are:
(iS)-(-)-l -phenylethylammonium ( ?)-3-(nitromethyl)hexanoate; quinidinium 7?)-3-(nitromethyl)hexanoate; and
(S)-(+)- l-cyclohexylethylammonium 7?)-3-(nitromethyl)hexanoate.
A further object of the invention is the use of a compound of Formula (I) or a compound of Formula (II) as defined above to prepare Brivaracetam.
One embodiment of the process according to the invention using the intermediates (R)- 3-(nitromethyl)hexanoic acid, 7^-3-(nitromethyl)hexanoate. (S)-(-)-\ - phenylethylammonium and methyl ( ?J-3-(nitromethyl)hexanoate is shown graphically in Schemes 1 and 2.
Detailed description of the invention
The order of addition of the solvents, raw materials, acids or bases may differ from that reported below.
In one embodiment of the invention, the process is conducted as follows:
Step a): 1 mole of /7-<3«5-2-hexen-l-al is reacted with 3-10 moles of nitromethane, preferably 5-7 moles, in the presence of 0.01-0.1 moles, preferably 0.03-0.07 moles, of a catalyst selected from 5,)-(-)-a,a-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether, /. /-(~)-a,a-diphenyl-2-pyrrolidinemethanol /<?r/-butyldimethylsilyl ether, and (S)-(-)- 5- (2-pyrrolidinyl)-l//-tetrazole, preferably (57-(-)-a,a-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether, 0.1-0.8 moles of boric acid, preferably 0.4-0.6 moles, and 0.01-0.1 moles of an organic acid, selected from pivalic, acetic, formic, citric and benzoic acid, preferably pivalic acid, in 2-50 volumes, preferably 5-20 volumes, of a solvent selected
from tetrahydrofuran, methanol, acetonitrile, ethanol, isopropanol, «-propanol, methyl- te/Y-butyl ether, diisopropyl ether, dichloromethane, methyltetrahydrofuran, ethyl acetate, isopropyl acetate, water or a mixture consisting of at least two of them, preferably a tetrahydrofuran/water mixture, in a v/v ratio ranging from 50/1 to 1/1, preferably from 20/1 to 5/1 , at a temperature ranging from -10 to +30°C, preferably from +10 to +25°C. The product ( ?)-3-(nitromethyl)hexanal is obtained in the enantiomeric ratio R : S = 97 : 3.
Step bl): 1 mole of (7?)-3-(nitromethyl)hexanal is dissolved in 5-50 volumes, preferably 10-20 volumes, of an acetonitrile/water mixture in a v/v ratio ranging from 10/1 to 1/1 , in the presence of an additive selected from dimethylsulphoxide, sulphamic acid and 30-35% hydrogen peroxide in water in the quantity of 1 -10 moles, preferably 2-5 moles. 1-5 moles of monobasic potassium phosphate, preferably 2-3 moles, and 1 -5 moles of sodium chlorite (25% w/w aqueous solution), preferably 2-3 moles, are added to the mixture at a temperature ranging from -10 to +20°C, preferably from -5 to +10°C. 0.001 - 0.01 moles of concentrated sulphuric acid, preferably 0.003-0.006 moles, are added to 1 mole of the product (7?)-3-(nitromethyl)hexanoic acid (in the enantiomeric ratio R : S = 97 : 3), dissolved in 1-30 volumes, preferably 2-10 volumes, of a solvent selected from methanol, ethanol, isopropanol, /7-propanol and te/7-butanol, preferably methanol, at a temperature ranging from +20 to +60°C, preferably from +30 to +50°C. The product methyl (7?)-3-(nitromethyl)hexanoate is obtained in the enantiomeric ratio R : S = 97 : 3.
Step b2) 1 mole of ( ?)-3-(nitromethyl)hexanal is dissolved in 5-50 volumes, preferably 10-20 volumes, of a solvent selected from methanol, ethanol, isopropanol, 77- propanol and /er/-butanol, preferably methanol, and 1-3 moles of N-bromosuccinimide, preferably 1.3-1.7 moles, are added at a temperature ranging from -5 to +10°C, preferably from 0 to +5°C. The product methyl (i?/-3-(nitromethyl)hexanoate is obtained in the enantiomeric ratio R : S = 97 : 3.
If it is decided to salify the ( ?)-3-(nitromethyl)hexanoic acid before completing step bl), 1 mole of acid is dissolved in 1-20 volumes, preferably 2-10 volumes, of a
solvent selected from methanol, ethanol, isopropanol, «-propanol, ethyl acetate, isopropyl acetate, dichloromethane and toluene, preferably methanol, at a temperature ranging from 10 to 50°C, preferably from 20 to 40°C. A base suitably selected from (S)-(-)- 1- phenylethylamine, (/?)-(-)- l -phenylethylamine, quinine, quinidine, cinchonine, cinchonidine, triethylamine, diethylamine, methylamine, ammonia, diisopropylethylamine, dicyclohexylamine, benzylamine, morpholine, guanidine, pyrrolidine, l ,8-diazabicyclo[5.4.0]undec-7-ene, l ,4-diazabicyclo[2.2.2]octane, 1 ,5,7- triazabiciclo[4.4.0]dec-5-ene and (S)-(+)- l-cyclohexylethylamine, (7?)-(-)-l- . cyclohexylethylamine, preferably (¾)-(-)- 1 -phenylethylamine 0.8-1. moles, preferably 0.9- 1.2 moles, is added to the solution, and 1-20 volumes, preferably 2-10 volumes, of a solvent suitably selected from diisopropyl ether, cyclopentyl methyl ether and methyl- /e/7-butyl ether, preferably diisopropyl ether, are dripped in. Using (£)-(-)- 1 - phenylethylamine, the product (£)-(-)- l -phenylethylammonium (R)- 3-
(nitromethyl)hexanoate is obtained in the enantiomeric ratio R : S > 99.5 : 0.5.
The salt is released by suspending 1 mole thereof in 1-20 volumes, preferably 2-10 volumes, of a solvent selected from methyl-/er/-butyl ether, diisopropyl ether and cyclopentyl methyl ether, preferably methyl-/cr/-butyl ether, to which a dilute aqueous solution of HC1 is added such that the quantity of HC1 is from 1 to 3 moles, preferably from 1.1 to 1.5 moles.
0.001-0.01 moles of concentrated sulphuric acid, preferably 0.003-0.006 moles, is added at a temperature ranging from +20 to +60°C, preferably from +30 to +50°C, to 1 mole of the product (7?/)-3-(nitromethyl)hexanoic acid (in the enantiomeric ratio R : S > 99.5 : 0.5), dissolved in a solvent selected from methanol, ethanol, isopropanol, n- propanol and /c;7-butanol, preferably methanol. The product methyl (R)-3- (nitromethyl)hexanoate is obtained in the enantiomeric ratio R : S > 99.5 : 0.5.
Step c): 1 mole of methyl (7? -3-(nitromethyl)hexanoate is dissolved in 2-30 volumes, preferably 3-10 volumes, of a solvent selected from dimethylsulphoxide, N,N- dimethylacetamide and N,N-dimethylformamide, preferably dimethylsulphoxide; 5-20
moles, preferably 8-15 moles, of an acid selected from acetic, formic and citric acid, preferably acetic acid, and 1.5-5 moles of sodium nitrite, preferably 2-4 moles, are added to the solution, and the mixture is heated to a temperature ranging from 20 to 50°C, preferably from 30 to 40°C. The product (7?)-2-(2-methoxy-2-oxoethyl)pentanoic acid is obtained, either in the enantiomeric ratio R : S = 97 : 3 (if the (/? -3-(nitromethyl)hexanoic acid has not been salified), or in the enantiomeric ratio R : S > 99.5 : 0.5 if the (R)-3- (nitromethyl)hexanoic) acid has been salified.
Step dl): 1 mole of (7? -2-(2-methoxy-2-oxoethyl)pentanoic acid is dissolved in 2- 30 volumes, preferably 5-20 volumes, of a solvent selected from tetrahydrofuran, methyltetrahydrofuran, toluene, dichloromethane, hexane, cyclohexane, pentane and heptane, preferably tetrahydrofuran, the solution is cooled to a temperature ranging from - 30 to +l0°C, preferably from -25 to +5°C, and 1-5 moles of borane-dimethylsulphide complex, preferably 1.2-3 moles, are added. The product (7? -4-propyldihydrofuran- 2(3H)-one is obtained, either in the enantiomeric ratio R : S = 97 : 3 (if the (R)- 3- (nitromethyl)hexanoic acid has not been salified), or in the enantiomeric ratio R : S > 99.5 : 0.5 (if the ( ? -3-(nitromethyl)hexanoic) acid has been salified).
Step d2): 1 mole of (7?)-2-(2-methoxy-2-oxoethyl)pentanoic acid is dissolved in 2- 30 volumes, preferably 5-20 volumes, of a solvent selected from tetrahydrofuran, methyltetrahydrofuran, toluene and dichloromethane, preferably tetrahydrofuran, at a temperature ranging from -30 to 0°C, preferably from -25 to -l0°C, and 1-3 moles, preferably 1.1-2 moles, of a reagent selected from ethyl chloroformate and isobutyl chloroformate, preferably isobutyl chloroformate, and 1-3 moles, preferably 1.1-2 moles, of a reagent selected from N-methylmorpholine, triethylamine and diisopropylethylamine, preferably N-methylmorpholine, are added. The progress of the reaction is monitored by 'H-NMR analysis. After filtration of the resulting suspension, at a temperature ranging from -10 to +l0°C, preferably from -5 to +5°C, 1-5 moles, preferably 1.2-3.5 moles, of sodium borohydride are added, followed by the addition of 1-20 moles, preferably 2-10 moles, of methanol. The progress of the reaction is monitored by 'H-NMR analysis. The
reaction mixture containing the non-isolated intermediate methyl (R)- 3- (hydroxymethyl)hexanoate is concentrated, diluted with a solvent selected from dichloromethane, tetrahydrofuran, methyltetrahydrofuran, toluene, isopropyl acetate and ethyl acetate, preferably dichloromethane, and treated with 0.1 -0.5 moles of an acid selected from -toluenesulphonic, trifluoroacetic, hydrochloric, sulphuric, formic, acetic and citric acid, preferably -toluenesulphonic acid, at a temperature ranging from -20 to +40°C, preferably from -5 to 25°C. The progress of the reaction is monitored by 'H-NMR analysis, while the enantiomeric ratio of the product (7?)-4-propyldihydrofuran-2(3H)-one (R : S = 97 : 3; R : S > 99.5 : 0.5 from salt) is monitored by chiral stationary phase gas chromatography.
The invention is illustrated in detail in the examples below.
Example 1 - step a)
10 g of /ra«s-2-hexen-l-al (101.9 mmols) is dissolved in 150 mL of a 7/1 v/v THF/H2O mixture, 1.66 g of (S)-(-)-a,a-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether (5.1 mmols), 3.15 g of boric acid (50.1 mmols) and 0.52 g of pivalic acid (5.1 mmols) are added, and the mixture is stirred at 20°C for 15 minutes. 37.3 g of nitromethane (61 1.4 mmols) is then added, and the mixture is stirred at 20°C for 48 h. When conversion is complete, tetrahydrofuran is removed under vacuum (T < 30°C) and isopropyl acetate (60 mL) is added. The resulting organic phase is washed with a 10% NaCl aqueous solution (x3) and a 5% NaHC03 aqueous solution (xl), before being concentrated at low pressure (T < 30°C) to obtain 12.5 g of ( ?)-3-(nitromethyl)hexanal (yield 77%). The enantiomeric ratio of the product (R : S = 97 :3) is monitored by chiral stationary phase gas chromatography.
'H-NMR (CDCb, 400 MHz, the chemical shifts expressed in ppm relate to the TMS signal): d 9.79 (s, 1H), 4.48 - 4.42 (m, 2H), 2.76 - 2.71 (m, 1H), 2.68 - 2.64 (m, 1 H), 2.61 - 2.56 (m, 1H), 1.44 - 1.36 (m, 4H), 0.98 (t, .7 = 5.6 Hz, 3H).
13C-NMR (CDCb, 100 MHz): 5 200.0, 78.5, 45.4, 33.7, 31.8, 19.7, 13.9.
Example 2 - step bl) without salification (synthesis of the acid)
20 g of (7?)-3-(nitromethyl)hexanal (125.6 mmols) is dissolved in 300 mL of a 5/1 CH3CN/H20 mixture, and the solution is cooled to 5°C. 29.4 g of DMSO (376.8 mmols) and 37.7 g of NaH2P04 (314 mmols) are then added, and 100 g of a 25% w/w NaC102 aqueous solution (276.3 mmols) is dripped in over the period of an hour. At the end of dripping the reaction mixture is further stirred for an hour at the same temperature. When conversion is complete, acetonitrile is removed at low pressure, and 100 mL of methyl- /er/-butyl ether is added. The resulting organic phase is washed with a 10% NaCl aqueous solution (x3) before being concentrated at low pressure to obtain 19.1 g of (R)-3- (nitromethyl)hexanoic acid (yield 87%).
The enantiomeric ratio of the product (R : S = 97 : 3) is monitored by chiral stationary phase liquid chromatography.
'H-NMR (CDC13, 400 MHz, the chemical shifts expressed in ppm relate to the TMS signal): d 4.55 - 4.42 (m, 2H), 2.70 - 2.59 (m, 1 H), 2.52 (d, J = 6.6 Hz, 2H), 1.48 - 1.32 (m, 4H), 0.94 (t, J= 6.9 Hz, 3H).
I3C-NMR (CDCl3, 100 MHz): d 177.2, 78.3, 35.4, 33.7, 33.5, 19.7, 13.8.
Example 3 - step bl) without salification (synthesis of the ester)
54 mg of concentrated sulphuric acid (0.55 mmols) is added to a solution of 19.1 g of (R)- 3-(nitromethyl)hexanoic acid (109 mmols) in 90 mL of methanol, and the mixture is stirred at 40°C for 2 h. When conversion is complete, methanol is removed at low pressure and methyl-/er/-butyl ether (100 mL) and water (100 mL) are added. After phase separation, the organic phase is concentrated at low pressure to obtain 20.2 g of methyl ( ?)-3-(nitromethyl)hexanoate (yield 98%).
The enantiomeric ratio of the product (R : S = 97 : 3) is monitored by chiral stationary phase liquid chromatography.
'H-NMR (CDC13, 400 MHz, the chemical shifts expressed in ppm relate to the TMS signal): d 4.55 - 4.40 (m, 2H), 3.70 (s, 3H), 2.69 - 2.59 (m, 1H), 2.45 (d, J = 6.7 Hz, 2H), 1.43 - 1.34 (m, 4H), 0.93 (t, J= 6.9 Hz, 3H).
13C-NMR (CDCb, 100 MHz): d 172.0, 78.5, 52.8, 35.7, 34.0, 33.6, 19.7, 13.9.
Example 4 - step b2) (synthesis of the ester)
10 g of (7?)-3-(nitromethyl)hexanal (62.8 mmols) is dissolved in 50 mL of methanol, and the solution is cooled to 5°C. 16.8 g of N-bromosuccinimide (94.2 mmols) is then added, and the mixture is stirred for 16 h at the same temperature. When conversion is complete, methanol is removed at low pressure, and methyl- /V-butyl ether (50 mL), water (50 mL) and 6.0 g of sodium thiosulphate (37.7 mmols) are added. After phase separation, the organic phase is concentrated at low pressure to obtain 9.9 g of methyl (7? -3-(nitromethyl)hexanoate (yield 84%).
Example 5 - step bl) with salification (synthesis of the salt of the acid)
20 g of (7?)-3-(nitromethyl)hexanal (125.6 mmols) is dissolved in 300 mL of a 5/1 CH3CN/H20 mixture, and the solution is cooled to 5°C. 29.4 g of DMSO (376.8 mmols) and 37.7 g of NaH2P04 (314 mmols) are then added, and 100 g of a 25% w/w NaCl02 aqueous solution (276.3 mmols) is dripped in over the period of an hour. At the end of dripping the reaction mixture is further stirred for an hour at the same temperature. When conversion is complete, acetonitrile is removed at low pressure, and 100 mL of methyl- /erl-butyl ether is added. The resulting organic phase is washed with a 10% NaCl aqueous solution (x3) before being concentrated at low pressure to obtain 19.1 g of (R)-3- (nitromethyl)hexanoic acid. The compound is dissolved in 45 mL of methanol, added with 13.2 g of (¾)-(-)- l-phenylethylamine (109.0 mmols), and the solution is heated to the temperature of 30°C. 70 mL of diisopropyl ether is added, and the resulting suspension is further stirred for 2 h before being filtered. The resulting solid is washed with diisopropyl ether (2 x 10 mL) and dried under vacuum at 30°C. 27.9 g of (R)- 3- (nitromethyl)hexanoate (^-(-H -phenylethylammonium is obtained (yield on starting aldehyde 75%).
The enantiomeric ratio of the product (R : S > 99.5 : 0.5) is monitored by chiral stationary phase liquid chromatography.
'H-NMR (CDC13, 400 MHz, the chemical shifts expressed in ppm relate to the
TMS signal): d 7.41 - 7.27 (m, 5H), 6.33 (broad s, 3H), 4.43 - 4.34 (m, 1 H), 4.32 - 4.19 (m, 2H), 2.53 - 2.42 (m, 1H), 2.19 (dd, J = 16.2, 5.2 Hz, 1 H), 2.07 (dd, J = 16.2, 8.2 Hz, 1H), 1.53 (d, J = 6.9 Hz, 3H), 1.38 - 1.24 (m, 4H), 0.97 - 0.83 (m, 3H).
13C-NMR (CDCh, 100 MHz): d 177.0, 141.9, 128.9 (2C), 128.1 , 126.3 (2 C), 79.1 , 51.1 , 37.7, 34.5, 33.8, 22.5, 19.6, 14.0.
Example 6 - step bl) with liberation of the salt (acid and ester synthesis with greater optical purity)
27.9 g of (7?)-3-(nitromethyl)hexanoate (¾)-(-)- l-phenylethylammonium (94.1 mmols) is suspended in 50 mL of methyl -/«7-butyl ether, 40 mL of an aqueous solution of 0.1N HC1 is added to the suspension, and the two-phase mixture is vigorously stirred for 30 minutes so that the two phases come into contact. The phases are then separated, and the organic phase is concentrated to obtain 15.7 g of ( ?)-3-(nitromethyl)hexanoic acid (yield 95%).
The enantiomeric ratio of the product ( R : S > 99.5 : 0.5) is monitored by chiral stationary phase liquid chromatography.
44 mg of concentrated sulphuric acid (0.45 mmols) is added to a solution of 15.7 g of (7?J-3-(nitromethyl)hexanoic acid (89.6 mmols) in 70 mL of methanol, and the mixture is stirred at 40°C for 2 h. When conversion is complete, methanol is removed at low pressure and methyl-/«7-butyl ether (70 mL) and water (70 mL) are added. After phase separation, the organic phase is concentrated at low pressure to obtain 16.6 g of methyl ( ? -3-(nitromethyl)hexanoate (yield 98%).
The enantiomeric ratio of the product ( R : S > 99.5 : 0.5) is monitored by chiral stationary phase liquid chromatography.
Example 7 - step c)
15 g of methyl ( ?)-3-(nitromethyl)hexanoate (79.3 mmols) is dissolved in 90 mL of DMSO; 47.4 g of acetic acid (790.3 mmols) and 16.4 g of sodium nitrite (237.9 mmols) are added to the solution, and the mixture is stirred for 6 h at 35°C. When conversion is complete, the mixture is cooled to 25°C, 250 mL of methyl-/er/-butyl ether
and 250 mL of water are added, and the mixture is stirred vigorously for 30 minutes. After phase separation, the organic phase is washed with water (3 x 50 mL) and concentrated at low pressure to obtain 1 1.1 g of (7? -2-(2-methoxy-2-oxoethyl)pentanoic acid (yield 80%).
The enantiomeric ratio of the product (R : S = 97 : 3 without salification; R : S >
99.5 : 0.5 from salt) is monitored by chiral stationary phase liquid chromatography.
'H-NMR (CDC13, 400 MHz, the chemical shifts expressed in ppm relate to the TMS signal): d 3.69 (s, 3H), 2.93 - 2.94 (m, 1H), 2.73 (dd, J = 17.0, 9.1 Hz, 1H), 2.46 (dd , J = 17.0, 4.6 Hz, 1 H), 1.74 - 1.63 (m, 1 H), 1.59 - 1.47 (m, 1H), 1.44 - 1.33 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).
13C-NMR (CDCb, 100 MHz): d 180.3, 172.4, 51.9, 40.8, 35.5, 33.9, 20.1 , 13.8.
Example 8 - step dl)
10 g of (7?)-2-(2-methoxy-2-oxoethyl)pentanoic acid (57.4 mmols) is dissolved in 70 mL of THF, and the solution is cooled to -20°C. 43.1 mL of 2M borane- dimethylsulphide complex in THF (86.1 mmols) is then dripped in over the period of 1 h at the same temperature. At the end of the addition, the temperature is left to rise to 0°C in 2 h. When conversion is complete, 30 mL of MeOH is added at the same temperature in 1 h, after which the solvents are removed at low pressure. 50 mL of methyl-Ze/ -butyl-ether and 50 mL of water are then added, and the mixture is stirred vigorously so that the phases come into contact. After phase separation, the organic phase is concentrated at low pressure to obtain 6.6 g of (7?)-4-propyldihydrofuran-2(3H)-one (yield 90%).
The enantiomeric ratio of the product (R : S = 97 : 3 without salification; R : S > 99.5 : 0.5 from salt) is monitored by chiral stationary phase gas chromatography.
'H-NMR (CDCb, 400 MHz, the chemical shifts expressed in ppm relate to the TMS signal): d 4.45 - 4.38 (m, 1 H), 3.96 - 3.89 (m, 1H), 2.65 - 2.54 (m, 2H), 2.19 (dd, J = 16.3, 7.3 Hz, 1 H), 1.48 - 1.44 (m, 2H) 1.40 - 1.30 (m, 2H) 0.95 (t, = 7. l Hz, 3H).
13C-NMR (CDCb, 100 MHz): d 177.3, 73.4, 35.4, 35.2, 34.5, 20.5, 13.9.
Example 9 - step d2)
10 g of (7?,)-2-(2-methoxy-2-oxoethyl)pentanoic acid (57.4 mmols) is dissolved in 70 mL of THF, and the solution is cooled to -20°C. 8.6 g of isobutyl chloroformate (63.1 mmols) is then added, and 7.0 g of N-methylmorpholine (68.9 mmols) is also added in 30 min. After completion of the addition, the resulting suspension is filtered to remove the morpholinium salts, and 4.3 g of sodium borohydride (1 14.8 mmols) is added in portions to the filtrate at 0°C, followed by 5 mL of MeOH, dripped in at the same temperature in 30 minutes. When conversion is complete, 30 mL of a 2N HC1 aqueous solution is added, and the mixture is stirred at 20°C for 30 minutes, before concentrating the organic solvents at low pressure and adding 50 mL of dichloromethane. After phase separation, 2.2 g of ara-toluenesulphonic acid monohydrate (1 1.5 mmols) at 0°C is added to the organic phase, containing a mixture of methyl (R)-3- (hydroxymethyl)hexanoate (therefore not isolated) and 7?)-4-propyldihydrofuran-2(3H)- one (already partly cyclised by the preceding addition of HC1), and the mixture is stirred at the same temperature for 4 h. When conversion is complete, 30 mL of a 5% NaHC03 aqueous solution is added, and the mixture is vigorously stirred so that the phases come into contact. After phase separation, the organic phase is concentrated at low pressure to obtain 6.0 g of (7?)-4-propyldihydrofuran-2(3H)-one (yield 82%).
Example 10
15 g of ( ?)-3-(nitromethyl)hexanoic acid (85.6 mmols) is dissolved in 35 mL of methanol, added with 27.8 g of quinidine (85.6 mmols), and the solution is heated to the temperature of 30°C. 70 mL of diisopropyl ether is added, and the resulting suspension is further stirred for 2 h before being filtered. The resulting solid is washed with diisopropyl ether (2 x 10 mL) and dried under vacuum at 30°C. 33.9 g of (7? -3-(nitromethyl)- hexanoate quinidinium is obtained (yield 80%).
The enantiomeric ratio of the product (R : S > 99.5 : 0.5) is monitored by chiral stationary phase liquid chromatography.
Example 11
15 g of ( ? -3-(nitromethyl)hexanoic acid (85.6 mmols) is dissolved in 35 mL of methanol, added with 10.9 g of (S)-(+)- l-cyclohexylethylamine (85.6 mmols), and the solution is heated to the temperature of 30°C. 70 mL of diisopropyl ether is added, and the resulting suspension is further stirred for 2 h before being filtered. The resulting solid is washed with diisopropyl ether (2 x 10 mL) and dried under vacuum at 30°C. 21.2 g of (7? -3-(nitromethyl)hexanoate (5')-(+)-l-cyclohexylethylammonium is obtained (yield 82%).
The enantiomeric ratio of the product (R : S > 99.5 : 0.5) is monitored by chiral stationary phase liquid chromatography.
Claims
1. A process for the preparation of (i?)-4-propyldihydrofuran-2(3H)-one
comprising the following steps:
a) asymmetric addition reaction of nitromethane to tram-2- hexen-l -al to give (R)-3- (nitromethyl)hexanal, wherein said asymmetric addition reaction is carried out in the presence of a catalyst selected from (S -(-)-a,a-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether, (5)-(-)-a,a-diphenyl-2-pyrrolidinemethanol tert- butyldimethylsilyl ether and (S)-(-)-5-(2-pyrrolidinyl)-l//-tetrazole, and in the presence of weak acids;
b) conversion of (i?)-3-(nitromethyl)hexanal to a C1-C4 alkyl (R)- 3-
(nitromethyl)hexanoate by means of:
bl) reaction of (/?)-3-(nitromethyl)hexanal with aqueous sodium chlorite to give (/?)-3-(nitromethyl)hexanoic acid, which is subjected to Fischer esterification in a C1-C4 alkyl alcohol to give said C1-C4 alkyl ( R)-3 - (nitromethyl)hexanoate; or
b2) direct oxidation of (i?)-3-(nitromethyl)hexanal with N-bromosuccinimide in a C1-C4 alkyl alcohol to give said C1-C4 alkyl (R)- 3-
(nitromethyl)hexanoate;
c) reaction of said C1-C4 alkyl ( ?)-3-(nitromethyl)hexanoate in the presence of sodium nitrite and acetic acid to give an (R)- 2-(2-(CI-C4 alkoxy)-2- oxoethyljpentanoic acid;
d) cyclisation of said ( ?)-2-(2-(C I-C4 alkoxy)-2-oxoethyl)pentanoic acid to (R)-4-
propyldihydrofuran-2(3H)-one:
dl) directly, by reaction with borane-dimethylsulphide complex; or d2) by previous reduction to give a Ci-C4 alkyl (R)- 3-
(hydroxymethyl)hexanoate by reacting with sodium borohydride the mixed anhydride obtained by reaction of said (i?)-2-(2-(Ci-C4 alkoxy)-2- oxoethyl)pentanoic acid with an alkyl chloroformate selected from ethyl chloroformate and isobutyl chloroformate in the presence of a base selected from N-methylmorpholine, triethylamine and diisopropylethylamine, said reduction being followed by acid-catalysed cyclisation to give ( R)-4 - propyldihydrofuran-2(3H)-one.
2. The process according to claim 1 , wherein in step a) the enantiomeric ratio of (7?)-3-(nitromethyl)hexanal to (5)-3-(nitromethyl)hexanal is 97:3.
3. The process according to claim 1 , wherein in step bl) (7?)-3-(nitromethyl)hexanoic acid is isolated by conversion to a salt with a base selected from (5)-(-)-l- phenylethylamine, (R)-(-)-l-phenylethylamine, quinine, quinidine, cinchonine, cinchonidine, triethylamine, diethylamine, methylamine, ammonia, diisopropylethylamine, dicyclohexylamine, benzylamine, morpholine, guanidine, pyrrolidine, l ,8-diazabicyclo[5.4.0]undec-7-ene, l ,4-diazabicyclo[2.2.2]octane, 1 ,5,7- triazabicyclo[4.4.0]dec-5-ene, (5)-(+)-l-cyclohexylethylamine and (/?)-(-)- 1- cyclohexylethylamine, preferably (S)-(-)-l-phenylethylamine, followed by isolation of said salt and release of (7?)-3-(nitromethyl)hexanoic acid from said salt by reaction with hydrochloric acid.
4. The process according to claims 1 to 3 comprising the following steps:
a) asymmetric addition reaction of nitromethane to /n s-2-hexen-l-al to give (R)- 3- (nitromethyl)hexanal, wherein said asymmetric addition reaction is carried out in the presence of (5)-(-)-a,a-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether, boric acid and an organic acid selected from pivalic, acetic, formic, citric and benzoic acid, preferably pivalic acid;
b) conversion of (i?)-3-(nitromethyl)hexanal to methyl (i?)-3- (nitromethyl)hexanoate by means of:
bl) reaction of ( ?)-3-(nitromethyl)hexanal with aqueous sodium chlorite in the presence of an additive selected from dimethylsulphoxide, sulphamic acid and hydrogen peroxide to give (i?)-3-(nitromethyl)hexanoic acid, followed by Fischer esterification with methanol to give said methyl (7?)-3- (nitromethyl)hexanoate; or
b2) direct oxidation of (/?)-3-(nitromethyl)hexanal with N-bromosuccinimide in methanol to give said methyl (7?)-3-(nitromethyl)hexanoate;
c) reaction of said methyl (7?)-3-(nitromethyl)hexanoate in the presence of sodium nitrite and acetic acid to give (/?)-2-(2-methoxy-2-oxoethyl)pentanoic acid;
d) cyclisation of said ( ?)-2-(2-methoxy-2-oxoethyl)pentanoic acid to ( ?)-4- propy ldihydrofuran-2(3 H)-one :
dl ) directly, by reaction with borane-dimethylsulphide complex; or d2) by previous reduction to methyl ( ?)-3-(hydroxymethyl)hexanoate by reacting with sodium borohydride the mixed anhydride obtained by reaction of (i?)-2-(2-methoxy-2-oxoethyl)pentanoic acid with isobutyl chloroformate in the presence of N-methylmorpholme, said reduction being followed by acid-catalysed cyclisation.
5. The process according to claim 4, wherein in step bl) (i?)-3-(nitromethyl)hexanoic acid is isolated by conversion to the salt with (S)-(-)- 1 -phenylethylamine, followed by isolation of said salt and release of (i?)-3-(nitromethyl)hexanoic acid from said salt by reaction with hydrochloric acid.
6. The process according to claim 5, wherein ( ?)-3-(nitromethyl)hexanoic acid and its salt with (S)-(-)-l -phenylethylamine are isolated with an R : S enantiomeric ratio higher than 99.5 : 0.5.
7. A compound of Formula (I)
wherein R is selected from hydrogen and straight or branched C1-C4 alkyl.
8. A compound according to claim 5 selected from:
(Z?)-3-(nitromethyl)hexanoic acid; and
methyl (i?)-3-(nitromethyl)hexanoate.
9. A compound of Formula (II)
wherein A+ is the protonated form of a base selected from (S)-(-)-l - phenylethylamine, (./?)-(-)- 1-phenylethylamine, quinine, quinidine, cinchonine, cinchonidine, triethylamine, diethylamine, methylamine, ammonia, diisopropylethylamine, dicyclohexylamine, benzylamine, morpholine, guanidine, pyrrolidine, l ,8-diazabicyclo[5.4.0]undec-7-ene, l ,4-diazabiciclo[2.2.2]octane,
I ,5,7-triazabicyclo[4.4.0]dec-5-ene, (S)-(+)-l -cyclohexylethylamine and (i?)-(-)-l - cyclohexylethylamine.
10. A compound according to claim 9 selected from:
(S)-(-)-l-phenylethylammonium (i?)-3-(nitromethyl)hexanoate;
quinidinium (/?)-3-(nitromethyl)hexanoate; and
(5)-(+)-l -cyclohexylethylammonium (i?)-3-(nitromethyl)hexanoate.
II. Use of a compound of Formula (I) as defined in claims 7 and 8 or of a compound of Formula (II) as defined in claims 9 and 10 for the preparation of Brivaracetam.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT102018000006320A IT201800006320A1 (en) | 2018-06-14 | 2018-06-14 | PROCESS FOR THE ASYMMETRIC SYNTHESIS OF (R) -4-PROPYLDIHYDROFURAN-2 (3H) -ONE |
| IT102018000006320 | 2018-06-14 |
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| WO2019239341A1 true WO2019239341A1 (en) | 2019-12-19 |
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| PCT/IB2019/054907 Ceased WO2019239341A1 (en) | 2018-06-14 | 2019-06-12 | Process for asymmetric synthesis of (r)-4-propyldihydrofuran-2 (3h)-one |
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| IT (1) | IT201800006320A1 (en) |
| WO (1) | WO2019239341A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016191435A1 (en) * | 2015-05-25 | 2016-12-01 | Peng Wang | Processes to produce brivaracetam |
| CN106588831A (en) * | 2016-11-16 | 2017-04-26 | 上海博志研新药物技术有限公司 | Method for preparing furanone compounds |
| CN107698543A (en) * | 2017-11-14 | 2018-02-16 | 安徽华胜医药科技有限公司 | Preparation method of butyrolactone derivative |
| WO2018042393A1 (en) * | 2016-09-05 | 2018-03-08 | Micro Labs Limited | Novel process for the preparation of brivaracetam |
| CN108264495A (en) * | 2017-01-03 | 2018-07-10 | 重庆康施恩生物科技有限公司 | Bu Waxitan chiral intermediates and preparation method thereof |
-
2018
- 2018-06-14 IT IT102018000006320A patent/IT201800006320A1/en unknown
-
2019
- 2019-06-12 WO PCT/IB2019/054907 patent/WO2019239341A1/en not_active Ceased
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016191435A1 (en) * | 2015-05-25 | 2016-12-01 | Peng Wang | Processes to produce brivaracetam |
| WO2018042393A1 (en) * | 2016-09-05 | 2018-03-08 | Micro Labs Limited | Novel process for the preparation of brivaracetam |
| CN106588831A (en) * | 2016-11-16 | 2017-04-26 | 上海博志研新药物技术有限公司 | Method for preparing furanone compounds |
| CN108264495A (en) * | 2017-01-03 | 2018-07-10 | 重庆康施恩生物科技有限公司 | Bu Waxitan chiral intermediates and preparation method thereof |
| CN107698543A (en) * | 2017-11-14 | 2018-02-16 | 安徽华胜医药科技有限公司 | Preparation method of butyrolactone derivative |
Non-Patent Citations (1)
| Title |
|---|
| STUART CROSBY ET AL: "Intermediates for the Synthesis of 4-Substituted Proline Derivatives", SYNLETT, vol. 2010, no. 04, 10 February 2010 (2010-02-10), DE, pages 539 - 542, XP055539252, ISSN: 0936-5214, DOI: 10.1055/s-0029-1219372 * |
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