MX2007015724A - Processes forthe synthesis of 3-isobutylglutaric acid - Google Patents
Processes forthe synthesis of 3-isobutylglutaric acidInfo
- Publication number
- MX2007015724A MX2007015724A MXMX/A/2007/015724A MX2007015724A MX2007015724A MX 2007015724 A MX2007015724 A MX 2007015724A MX 2007015724 A MX2007015724 A MX 2007015724A MX 2007015724 A MX2007015724 A MX 2007015724A
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- Mexico
- Prior art keywords
- compound
- formula
- acid
- linear
- aryl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 102
- UATSLDZQNXAKMA-UHFFFAOYSA-N 3-(2-methylpropyl)pentanedioic acid Chemical compound CC(C)CC(CC(O)=O)CC(O)=O UATSLDZQNXAKMA-UHFFFAOYSA-N 0.000 title claims abstract description 79
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 17
- 238000003786 synthesis reaction Methods 0.000 title abstract description 14
- 230000002194 synthesizing Effects 0.000 title abstract description 13
- AYXYPKUFHZROOJ-ZETCQYMHSA-N (3S)-3-(aminomethyl)-5-methylhexanoic acid Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims abstract description 24
- 229960001233 pregabalin Drugs 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims description 206
- 239000000203 mixture Substances 0.000 claims description 87
- 238000006243 chemical reaction Methods 0.000 claims description 58
- 239000002253 acid Substances 0.000 claims description 57
- YGHRJJRRZDOVPD-UHFFFAOYSA-N Isovaleraldehyde Chemical compound CC(C)CC=O YGHRJJRRZDOVPD-UHFFFAOYSA-N 0.000 claims description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 41
- 125000003118 aryl group Chemical group 0.000 claims description 40
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 30
- 239000003495 polar organic solvent Substances 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 22
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N Dipropylamine Chemical group CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 21
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 18
- 239000011707 mineral Substances 0.000 claims description 18
- 150000007524 organic acids Chemical class 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 17
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 17
- 150000007529 inorganic bases Chemical class 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 239000001184 potassium carbonate Substances 0.000 claims description 15
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 14
- 150000007530 organic bases Chemical class 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- 230000003301 hydrolyzing Effects 0.000 claims description 11
- UAOMVDZJSHZZME-UHFFFAOYSA-N Diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 10
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- CPBZARXQRZTYGI-UHFFFAOYSA-N 3-cyclopentylpropylcyclohexane Chemical compound C1CCCCC1CCCC1CCCC1 CPBZARXQRZTYGI-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 229960000583 Acetic Acid Drugs 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- 239000005695 Ammonium acetate Substances 0.000 claims description 6
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 6
- 229940043376 ammonium acetate Drugs 0.000 claims description 6
- 235000019257 ammonium acetate Nutrition 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
- 229940043279 diisopropylamine Drugs 0.000 claims description 5
- 239000008079 hexane Substances 0.000 claims description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 5
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 235000011054 acetic acid Nutrition 0.000 claims description 4
- 238000005755 formation reaction Methods 0.000 claims description 4
- 239000001187 sodium carbonate Substances 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000005469 ethylenyl group Chemical group 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 230000002378 acidificating Effects 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- HRWKAVANDPWNCG-UHFFFAOYSA-L [Na+].[Cs+].OC([O-])=O.OC([O-])=O Chemical compound [Na+].[Cs+].OC([O-])=O.OC([O-])=O HRWKAVANDPWNCG-UHFFFAOYSA-L 0.000 claims 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 30
- 239000000543 intermediate Substances 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 11
- 238000007792 addition Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000003809 water extraction Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- GXHFUVWIGNLZSC-UHFFFAOYSA-N Meldrum's acid Chemical group CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 4
- XNINAOUGJUYOQX-UHFFFAOYSA-M 2-cyanobutanoate Chemical compound CCC(C#N)C([O-])=O XNINAOUGJUYOQX-UHFFFAOYSA-M 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 102000008214 Glutamate decarboxylases Human genes 0.000 description 3
- 108091022086 Glutamate decarboxylases Proteins 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 3
- 239000012455 biphasic mixture Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- -1 3- isobutylglutaric acid anhydride 3- isobutylglutaric acid Chemical compound 0.000 description 2
- 210000004556 Brain Anatomy 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N GABA Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 229960003692 aminobutyric acid Drugs 0.000 description 2
- 230000001773 anti-convulsant Effects 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QKCOIQXSGBCVSV-PKPIPKONSA-N (2S)-3-(aminomethyl)-2-methylhexanoic acid Chemical compound CCCC(CN)[C@H](C)C(O)=O QKCOIQXSGBCVSV-PKPIPKONSA-N 0.000 description 1
- LHSAKGVBHJUEOV-UHFFFAOYSA-N 2-(2-methylpropyl)pentanedioic acid Chemical compound CC(C)CC(C(O)=O)CCC(O)=O LHSAKGVBHJUEOV-UHFFFAOYSA-N 0.000 description 1
- NPDKTSLVWGFPQG-UHFFFAOYSA-N 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid Chemical compound CC(C)CC(CC(N)=O)CC(O)=O NPDKTSLVWGFPQG-UHFFFAOYSA-N 0.000 description 1
- XLSGYCWYKZCYCK-UHFFFAOYSA-N 4-(2-methylpropyl)oxane-2,6-dione Chemical compound CC(C)CC1CC(=O)OC(=O)C1 XLSGYCWYKZCYCK-UHFFFAOYSA-N 0.000 description 1
- 229940009697 Lyrica Drugs 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 210000000225 Synapses Anatomy 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 230000003556 anti-epileptic Effects 0.000 description 1
- 230000000949 anxiolytic Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 230000001737 promoting Effects 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Abstract
Provided are processes for the synthesis of 3-isobutylglutaric acid, an intermediate in the synthesis of (S)-Pregabalin.
Description
PROCESSES FOR THE SYNTHESIS OF 3-ISOBUTYLGLUTARIC ACID
Field of the Invention The invention comprises processes for the synthesis of 3-isobutylglutaric acid, an intermediate in the synthesis of (S) -Pregabalin.
Background of the Invention (S) -pregabalin, (S) - (+) - 3 - (aminomethyl) methylhexanoic acid, a compound having the chemical structure,
(S) -Pregabalin is an analogous acid? -amino butyric acid or (S) -3-isobutyl (GABA). It has been found that (S) -pregabalin activates GAD (glutamic acid decarboxylase). (S) -Pregabalin has a protective effect that depends on the dose, on the stroke attack and is an active compound of the CNS. (S) -Pregabalin is effective in anticonvulsant therapy, due to the activation of GAD, promoting the production of GABA, one of the neurotransmitters
Main inhibitors of the brain, which is released in 30 percent of the brain's synapses.
(S) -Pregabalin has analgesic, anticonvulsive and anxiolytic activity.
(S) -Pregabalin is marketed under the name LYRICA® by Pfizer, Inc. in tablets of 25, 50, 75, 150, 200 and 300 mg.
(S) -Pregabalin can be prepared by converting 3-isobutylglutaric acid to 3-isobutylglutaric anhydride, followed by amidation to obtain the corresponding 3- (carbamoylmethyl) -5-methylhexanoic acid (referred to as CMH). The CMH is then optimally resolved to provide (R) -CMH, which is converted by Hoffman reaction to (S) -Pregabalin. See L. Martin et al., "Pregabalin, Antiepileptic", Drugs of the Future, 24 (8): 862-870 (1999); United States of America No. 5,616,793. This process can be illustrated by the following Scheme 1.
Scheme 1. Preparation of (S) -Pregabalin
3- isobutylglutaric acid anhydride 3- isobutylglutaric acid C H
optical resolution
(S) -Pregabalin (R) -C H
3-Isobutylglutaric acid can be prepared by condensation of isovaleraldehyde and ethylcyanoacetate, followed by Michael addition, and hydrolysis. See Day and Thorpe, J. Chem. Soc, 117: 1465 (1920); J. Casson, et al., "Branched-Chain Fatty Acids, XXVII, Further Study of the Dependence of Rate of Amide Hydrolysis on Substitution near the Amide Group, Relative Rates of Hydrolysis of Nitrile to Amide and Amide to Acid," J. Org. Chem., 18 (9): 1129-1136 (1953); P.S. Theisen, et al., "Prochiral Recognition in the Reaction of 3- substituted Glutarxc Anhydrides with Chiral Secondary Alcohols" J.Org. Chem., 58 (1): 142-146 (1993); M.S. Hoekstra, et al., "Chemical Development of CI-1008,
an Enantiomerically Pure Anticonvulsant ", Organic Process Research &Development, 1 (1): 26-38 (1997) This process can be illustrated by the following Scheme 2.
burn 2; Preparation of 3- isobutylglutari acid
Inc
3- isobutylglutaric acid
This process is also disclosed in U.S. Patent No. 5,616,793 ("793 patent") and its corresponding International Publication O 96/38405 ("WO '405"). The "793 and WO" 405 patents disclose that the hydrolysis is complete after about 72 hours. Patent '793 col. 6, 11.30-32; WO '405, p.11, 11-, 17-19.
Thus, there is a need in the art for processes for the preparation of 3-isobutylglutaric acid which can be performed in shorter time periods than those of the prior art mentioned above.
EXAMPLE OF THE INVENTION In one embodiment, the invention comprises a process for preparing 3- isobutylglutaric acid comprising: (a) combining isovaleraldehyde, a compound of the following formula II,
Or a compound of the following formula III,
OR3 OI¾ DIO
Or a compound of the following formula IV,
° X ° IV
A non-polar organic solvent, and a first base to obtain a compound of formula V,
V composed of the following formula VIII
VIII composed of the following formula X,
X
Respectively; (b) combining a compound of formula IV with the compound of formula V, the compound of formula VIII, or the compound of formula X, an aprotic polar organic solvent, and a second base to obtain a compound of the following Formula VII,
VII
A compound of the following formula IX,
IX
Or a compound of the following formula XII,
XII
respectively; and (c) hydrolyzing the compound of the formula VII, the compound of the formula IX, or the compound of the formula XII to obtain 3- isobutylglutaric acid, characterized in that R is H, Ci-8 straight or branched alkyl or C6-i4 aril; Ri is H, CN, COOH, C00, Ci-8 alkyl, COOC6-i4 aryl or (R60) 2P = 0; R2 and R3 are independently H, C1-8 linear or branched, or C6-i4 aryl; R4 and R5 are independently H, Ci_8 straight or branched alkyl, or C6-i4 aryl; and R6 is C1-8 linear or branched alkyl or C6-i4 aryl.
In another embodiment, the invention encompasses a process for preparing 3- isobutylglutaric acid comprising: (a) combining isovaraldehyde, a compound of the following formula III,
III
A non-polar organic solvent, an organic acid, and an organic base to obtain a compound of the following formula VIII;
VIII
(b) combining the compound of the formula VIII with the compound of the formula III, an aprotic polar organic solvent, an inorganic base to obtain a compound of the following formula XIII; Y
XIII
hydrolyzing the compound of formula XIII to obtain isobutylglutaric acid, characterized in that R2 and R3 are
independently H, C1-8 linear or branched alkyl, or C6-i4 aryl.
In another embodiment, the invention comprises a process for preparing 3-isobutylglutaric acid comprising: (a) combining isovaleraldehyde, a compound of the following formula
III
an alcohol, ammonium acetate and ammonia to obtain a compound of the following formula XIV;
XIV Y (b) hydrolyze the compound of the formula XIV to obtain 3-isobutylglutaric acid characterized in that R2 and R3 are independently H, Ci-8 linear or branched alkyl, or C6-i4 aryl.
In another embodiment, the invention encompasses a process for the preparation of 3-isobutylglutaric acid comprising: (a) combining isovaleraldehyde, a compound of the following formula
a non-polar organic solvent, and a first base to obtain a compound of the following formula V;
v (b) combining the compound of the formula V with a compound of the following formula III
III
and a second base to obtain a compound of the following formula VI
SAW
; and (c) hydrolyzing the compound of the formula VI to obtain 3-isobutylglutaric acid, characterized in that R is H, Ci-8 linear or branched alkyl or C6-i4 aryl; Rx is H, CN, COOH, C00, Ci-8 alkyl, COOC6-i4 aryl or (R60) 2P = 0; R2 and R3 are independently H, Ci-8 linear or branched, or C6-i4 aryl; and R6 is Ci ÷ 8 linear or branched alkyl or C6-i4 aryl.
In another embodiment, the invention encompasses an intermediate compound of 3-isobutylglutaric acid of the following formula IX
Characterized in that R2 and R3 are independently H, Ci-8 linear or branched alkyl, or C6-i4 aryl; and R4 and R5 are independently H, straight or branched Ci-8 alkyl, or C6-14 aryl.
In another embodiment, the invention encompasses the preparation of 3-isobutylglutaric acid from the intermediate compound of formula IX.
In another embodiment, the invention encompasses the preparation of 3-isobutylglutaric acid from the intermediate compound of formula XII.
Characterized in that R 4 and R 5 are independently H, straight or branched Ci-8 alkyl, or C 6 -i 4 aryl.
In another embodiment, the invention encompasses the preparation of 3-isobutylglutaric acid from the intermediate compound of formula XII.
In another embodiment, the invention encompasses 3-isobutylglutaric acid intermediate compound of the following formula
XIII
XIII
Characterized in that R2 and R3 are independently H, Ci-8 linear or branched alkyl, or C6-i4 aryl.
In another embodiment, the invention encompasses the preparation of 3-isobutylglutaric acid from the intermediate compound of formula XIII.
In another embodiment, the invention encompasses 3-isobutylglutaric acid intermediate compound of the following formula XIV
XIV
Characterized in that R2 and R3 are independently H, Ci-8 linear or branched alkyl, or C6-aryl.
In another embodiment, the invention encompasses the preparation of 3-isobutylglutaric acid from the intermediate compound of formula XIV.
DETAILED DESCRIPTION OF THE INVENTION The invention addresses the defects of the aforementioned prior art by providing synthesis in a container of the intermediate 3-isobutylglutaric acid of pregabalin. These syntheses can be performed in shorter periods than those described above, and, thus, are more suitable for use on an industrial scale.
In one embodiment, the invention encompasses a synthesis of 3-isobutylglutaric acid (referred to as "Process No. 1") which can be illustrated by the following Scheme 3.
Scheme 3. Synthesis of 3-isobutylglutaric acid - Process No 1.
V
VI 3- isobutylglutaric acid
Characterized in that R is H, characterized in that R is H, Ci-8 linear or branched alkyl or C6-i4 aryl; Ri is H, CN, COOH, C00, Ci-8 alkyl, COOC6-i4 aryl or (R60) 2P = 0; R2 and R3 are independently H, linear or branched Ci-8, or C6-aryl; and R6 is Ci-8 linear or branched alkyl or C6-i4 aryl. Preferably, at least one of R, R2, and R3 is ethyl. Preferably Ri is cyano. Preferably, R6 is methyl, ethyl, or phenyl.
When R is ethyl and R x is CN, the compound of the formula ethyl cyanoacetate of the formula,
And the compound of formula V has the following structure.
When R2 and R3 are ethyl, the compound of formula III diethylmalonate of the formula.
OEt OEt
When R is ethyl, Rx is CN, and R2 and R3 are ethyl, the compound of formula VI has the following structure.
The process comprises: (a) combining isovaleraldehyde of the formula I, a compound of the formula II, an organic solvent not
polar, and a first base to obtain a compound of the formula V; (b) combining the compound of the formula V with a compound of the formula III and a second base to obtain a compound of the formula VI; and (c) hydrolyzing the compound of formula VI to obtain 3-isobutylglutaric acid.
The process can be carried out in a container, that is, without recovery of intermediates obtained during the process.
Preferably, the non-polar organic solvent is selected from a group consisting of C6-9 cyclic, branched or linear hydrocarbons and C6-9 aromatic hydrocarbons. Preferably, the linear or branched cyclic hydrocarbon C6-9 is hexane, heptane or cyclohexane, and more preferably cyclohexane. Preferably, the C6-9 aromatic hydrocarbon is toluene. More preferably, the non-polar organic solvent is a C6-9 linear or branched cyclic hydrocarbon and more preferably is cyclohexane.
The first and second base may be the same or different. Preferably, the first and second bases are organic or inorganic bases. Preferred organic bases are di-n-propylamine, triethylamine, piperidine, and diisopropylamine, and an even more preferred organic base is di-n-propylamine. Preferred inorganic bases are potassium carbonate, cesium carbonate and
sodium carbonate, and a preferred inorganic base is potassium carbonate. More preferably, the first and second bases are organic bases, and more preferably di-n-propylamine.
Commonly, the combination of step (a) is heated and the water is extracted azeotropically during the course of the reaction to promote the formation of the compound of formula V. Preferably, the combination of step (a) is heated to a temperature from about 20 ° C to about 90 ° C, more preferably about 50 ° G to 90 ° C, and more preferably about 70 ° C to 80 ° C. After the water is completely extracted the non-polar organic solvent is preferably extracted to obtain a concentrated mixture having the compound of formula V.
Commonly, the concentrated mixture having the compound of formula V is cooled before combining with the compound of formula III and the second base. Preferably, the concentrated mixture is cooled to a temperature of about 35 ° C to about 20 ° C, and more preferably at 30 ° C to about 25 ° C.
: Commonly, the combination of step (b) is heated to obtain a mixture having the compound of formula VI.
Preferably, the combination of step (b) is heated to a temperature of about 35 ° C to 60 ° C, more preferably to about 40 ° C to 60 ° C, and more preferably about 50 ° C to 55 ° C. Preferably the combination is heated for about 0.5 to 10 hours, and more preferably at 0.5 to 5 hours.
Commonly, the mixture having the compound of formula VI is cooled before hydrolysis. Preferably, the mixture having the compound of the formula VI is cooled to a temperature of about 50 ° C to 15 ° C, more preferably about 40 ° C to 20 ° C, and more preferably to about 30 ° C to 25 °.
Commonly, the compound of formula VI is hydrolyzed by combining with an acid and heating. Preferably, the acid is up mineral acid, an organic acid, or a mixture thereof. Preferably, the mineral acid is HC1, HBr, or sulfuric acid. Preferably, the organic acid is trifluoroacetic acid. More preferably, the acid is mineral acid, even more preferably HBr, HC1 or sulfuric acid, and more preferably, either HBr or HC1. Preferably, the acid is in the form of an aqueous solution.
Preferably, the combination of the compound of formula VI and the acid is heated to a temperature of about 80 ° C to 140 ° C to obtain 3-isobutylglutaric acid, more preferably 90 ° C to about 130 ° C, and more preferably about 100 ° C. ° C to 125 ° C. When the acid is HBr, preferably, the combination is heated for about 6 to 20 hours, more preferably for 6 to 16 hours, depending on the amount of acid used.
The thus obtained 3-isobutylglutaric acid can be recovered by cooling the resulting biphasic mixture to a temperature of about 30 ° C to 25 ° C, extracting the 3-isobutylglutaric acid from the mixture with toluene, and extracting the toluene to recover the 3- isobutylglutaric acid. . Preferably, the toluene is extracted by distillation.
Optionally, Process No 1 can be carried out in two steps instead of three, ie the isovaleraldehyde of the formula I, the compound of the formula II, and the compound of the formula III can be combined in a single step. The process comprises: (a) combining isovaleraldehyde of the formula I, a compound of the formula II, a compound of the formula III, a non-polar organic solvent, and a base to obtain a compound of the formula VI;
and (b) hydrolyzing the compound of formula VI to obtain 3- isobutylglutaric acid.
Preferably, the non-polar organic solvent, the base, and hydrolysis conditions are as described above.
Commonly, the compound of the formula I, the compound of the formula II, and the compound of the formula III are combined with a base, and with a non-polar organic solvent to obtain a first mixture. The first mixture is then heated and the water is extracted azeotropically during the course of the reaction. Preferably, the first mixture is heated to a temperature of about 40 ° C to 90 ° C and more preferably about 40 ° C to 45 ° C. After the water is completely extracted, an additional amount of base is preferably added to form a second mixture. The second mixture is then heated to obtain the compound of formula VI. Preferably, the second mixture is then heated to obtain the compound of the formula VI. Preferably, the second mixture is heated to a temperature of about 35 ° C to 60 ° C, more preferably about 40 ° C to 60 ° C, and more preferably 50 ° C to 55 ° C. Preferably, the second mixture is heated for 0.5 hours to about 6 hours and more preferably for 2 to 5 hours. Preferably, the solvent
Non-polar organic is extracted during heating to provide a second concentrated mixture. The second concentrated mixture is then cooled before hydrolysis. Preferably, the second mixture is cooled to a temperature of about 35 ° C to 0 ° C and more preferably about 35 ° C to 30 ° C.
Hydrolysis is commonly carried out by combining the second concentrated mixture with an acid and heating. The combination is preferably heated to a temperature of about 80 ° C to about 140 ° C more preferably 90 ° C to about 130 ° C and more preferably about 100 ° C to 125 ° C. Preferably, the combination is heated for about 2 to 20 hours, more preferably for 6 to 20 hours, and more preferably for 6 to 10 hours in the case of HBr.
In another embodiment, the invention encompasses synthesis of 3- isobutylglutaric acid (collectively referred to as "Process No 2") which can be illustrated by each of the three processes illustrated in the following. Scheme 4
Scheme 4. Synthesis of 3- isobutylglutaric acid- Process No 2 Route (i).
3- isobutylglutaric acid route! (ii)
acid 3- isofouti.g.utáiriice
Route (iii)
xii acid 3- isobetilgSuiíáóco
Characterized in that R is H, Ci_ 8 linear or branched alkyl or C6- i4 aryl; Ri is H, CN, COOH, C00, Ci_8 alkyl, C00Ce-i4 aryl or (R60) 2P = 0; R2 and R3 are independently H, Ci- 8 linear or branched, or C6-i4 aryl, R4 and R5 are independently H, Ci- 8 linear or branched, or C6-i4 aryl; and R6 is Ci- 8 linear or branched alkyl or C6-i4 aryl. Preferably, at least one of R, R2, and R3 is ethyl. Preferably, Ri is cyano. Preferably, at least one of R4, and R5 is methyl. Preferably, R6 is methyl, ethyl or phenyl.
When R4 and R5 are methyl, the compound of formula IV is 2,2-dimethyl-1,3-dioxane-4,6-dione of the formula
When R is Et, Rx is CN, and R4 and R5 are methyl, the compound of formula VII has the following structure.
When R2 and R3 are ethyl, the compound of formula VIII is the following structure.
When R4 and R5 are methyl, the compound of formula X has the following structure.
When R 4 and R 5 are methyl, the compound of formula XI has the following structure.
The process comprises: (a) combining isovaleraldehyde of the formula I, a compound of the formula II, a compound of the formula III, or a compound of the formula IV, a non-polar organic solvent, a first base to obtain a compound of the formula V, a compound of the formula VIII, or a compound of the formula X, respectively; (b) combining a compound of the formula IV with the compound of the formula V, the compound of the formula VIII, or the compound of the formula X, an aprotic polar organic solvent, and a second base to obtain a compound of the formula VII, a compound of the formula IX, or a compound of the formula XII, respectively; and (c) hydrolyzing the compound of the formula VII, the compound of the formula IX, or the compound of the formula XII to obtain 3-isobutylglutaric acid.
The process can be carried out in a container, that is, without recovering the intermediates obtained during the process.
Preferably, the non-polar organic solvent is selected from the group consisting of C6-9 linear, branched or cyclic hydrocarbons and aromatic C6-9 hydrocarbons. Preferably, the linear, branched or cyclic C6-g hydrocarbon is hexane, heptane or cyclohexane, and more preferably cyclohexane. Preferably, the aromatic C6-9 hydrocarbon is toluene. More preferably, the non-polar organic solvent is a linear, branched or cyclic C6-9 and more preferably cyclohexane.
The first and second base may be the same or different, and preferably they are different. Preferably, the first and second bases are organic or inorganic bases. The preferred inorganic bases are di-n-propylamine, triethylamine, piperidine, and diisopropylamine and a more preferred organic base is di-n-propylamine. Preferred inorganic bases are potassium carbonate, cesium carbonate and sodium carbonate and a preferred inorganic base is potassium carbonate. More preferably, the first base is an organic base, and more preferably di-n-propylamine. More preferably, the second base; it is an inorganic base, and more preferably potassium carbonate.
Preferably, the polar aprotic organic solvent is dimethylsulfoxide ("DMSO"), N-N-dimethylformamide ("DMF") or
dimethylacetamide ("DMA"). More preferably, the polar aprotic organic solvent is DMSO.
Commonly, the combination of step (a) is heated and the water is extracted azeotropically during the course of the reaction to promote the formation of the compound of formula V, the compound of formula VIII or the compound of formula X. Preferably, the combination of step (a) is heated to a temperature of about 40 ° C to 90 ° C more preferably about 50 ° C to 90 ° C and more preferably 70 ° C to 80 ° C. After the water is completely extracted, the non-polar organic solvent is preferably extracted to obtain a concentrated mixture having the compound of the formula V, the compound of the formula VIII, or the compound of the formula X.
! Commonly, the concentrated mixture having the compound of the formula V, the compound of the formula VIII, or the compound of the formula X is cooled before the combination with the polar aprotic organic solvent and the second base. Preferably, the concentrated mixture is cooled to a temperature of about 35 ° C to 20 ° C and more preferably to about 30 ° C to 25 ° C.
Commonly, the combination of step (b) is heated to obtain the compound of formula VII, the compound of
Formula IX, or the compound of formula XII. Preferably, the combination of step (b) is heated to a temperature of about 35 ° C to 60 ° C, more preferably about 40 ° C to 60 ° C, and more preferably about 50 ° C to 55 ° C. Preferably the combination is heated for about 0.5 to 10 hours and more preferably about 0.5 to 5 hours.
Commonly, the compound of the formula VII, the compound of the formula IX or the compound of the formula XII are hydrolyzed by combining with an acid and heated. Preferably, the acid is a mineral acid, an organic acid, or a mixture thereof.
Preferably, the mineral acid is HC1, HBr, or sulfuric acid.
Preferably, the organic acid is trifluoroacetic acid. More preferably, the acid is mineral acid, even more preferably HBr, HC1 or sulfuric acid, and more preferably, HBr or HC1. Preferably, the acid is in the form of an aqueous solution.
Preferably, the combination of the compound of the formula
VII, the compound of the formula IX or the compound of the formula XII and! the acid is heated to a temperature of 80 ° C to 140 ° C to obtain the 3- isobutylglutaric acid, more preferably about 90 ° C to 130 ° C and more preferably
about 100 ° C to about 125 ° C. Preferably, the combination is heated for 12 to 14 hours, more preferably 12 to 15 hours.
The 3-isobutylglutaric acid thus obtained can be recovered by cooling the resulting biphasic mixture at a temperature of about 30 ° C to 25 ° C, extracting the 3-isobutylglutaric acid from the mixture with toluene and extracting the toluene to recover the 3- isobutylglutaric acid. Preferably, the toluene is extracted by distillation.
The invention further comprises the intermediate compound of 3-isobutylglutaric acid of the following formula IX.
characterized in that R2 and R3 are independently H, Ci-8 linear or branched, or C6-14 aryl; and R4 and R5 are independently H, C1-a linear or branched, or C6-i4 aryl. Preferably, at least one of R2 and R3 is ethyl, and at least one
of R4 and R5 is methyl. When R2 and R3 are ethyl, and R4 and R5 are methyl, the compound of formula IX has the following structure.
The invention further encompasses the intermediate compound of 3-isobutylglutaric acid of the following formula XII.
characterized in that R4 and R5 are independently H, Ci-8 linear or branched, or C6-i4 aryl. Preferably, at least one of R4 and R5 is methyl. When R4 and R5 are methyl, the compound of formula XII has the following structure.
In another embodiment, the invention comprises a synthesis of 3-isobutylglutaric acid (referred to as "Process No. 3") which can be illustrated by the following Scheme 5.
Scheme 5. Synthesis of 3- isobutylglutaric acid- Process No 3.
VIII
3- isobutylglutaric acid XIII
Characterized in that R2 and R3 are independently H, C1-8 linear or branched alkyl, or C6-i4 aryl. Preferably, at least one of R2 and R3 is ethyl.
The process comprises: (a) combining isovaleraldehyde of the formula I, a compound of the formula III, a non-polar organic solvent, an organic acid, and an organic base to obtain a compound of the formula VIII; (b) combining the compound of formula VIII with a compound of formula III, an aprotic polar organic solvent, and an inorganic base to obtain a compound of formula XIII; and (c) hydrolyzing the compound of formula XIII to obtain 3- isobutylglutaric acid.
The process can be carried out in a container, that is, without recovering the intermediates obtained during the process.
Preferably, the non-polar organic solvent is selected from C6 + 9 linear or branched or cyclic hydrocarbons and C6-g aromatic hydrocarbons. Preferably, the C6-9 hydrocarbon is hexane, heptane or cyclohexane, and more preferably the C6-9 aromatic hydrocarbon is cyclohexane. Preferably, the C6-9 aromatic hydrocarbon is toluene. More preferably, the non-polar organic solvent is C6.s linear, branched or cyclic hydrocarbon and more preferably is cyclohexane.
Preferably, the organic base is di-n-propylamine, triethylamine, piperidine, or diisopropylamine and more preferably di-n-propylamine.
Preferably, the inorganic base is potassium carbonate, cesium carbonate or sodium carbonate, and more preferably potassium carbonate.
Preferably, the aprotic polar organic solvent is dimethylsulfoxide ("DMSO"), N-N-dimethylformamide ("DMF") or dimethylacetamide ("DMA"). More preferably, the polar aprotic organic solvent is DMSO.
Commonly, the combination of step (a) is heated and the water is extracted azeotropically during the course of the reaction to promote the formulation of the compound of formula VIII, Preferably, the combination of step (a) is heated to a temperature from about 20 ° C to 90 ° C, more preferably about 40 ° C to 90 ° C and even more preferably about 50 ° C to about 90 ° C, and more preferably about 70 ° C to about 80 ° C.
Commonly, the concentrated mixture having the compound of formula VIII is cooled before combining with the solvent
polar organic aprotic, the compound of formula III, and the inorganic base. Preferably, the concentrated mixture is cooled to a temperature of 35 ° C to about 20 ° C, and even more preferably 30 ° C to 25 ° C.
Commonly, the combination of step (b) is heated to obtain a mixture having the compound of formula XIII. Preferably, the combination of step (b) is heated to a temperature of about 20 ° C to 456 ° C and more preferably 25 ° C to about 30 ° C. Preferably, the combination is heated for 2 to 10 hours and more preferably for 4 to 6 hours.
Optionally, the process may further comprise, prior to hydrolysis: (a) cooling the mixture having the compound of formula XIII; (b) combining the mixture having the compound of the formula XIII with an alcohol and sodium hydroxide to obtain a mixture having a basic pH; (c) cooling the mixture having the basic pH; (d) combining the mixture having the basic pH with acid, glacial acetic and HCl to obtain a mixture having an acidic pH; and € extract alcohol.
Preferably, the mixture having the compound of the formula XIII is cooled to a temperature of about -5 ° C.
at -20 ° C, and more preferably at -5 ° C to -10 ° C. Preferably, the basic pH is from 7 to 10 and more preferably approximately 8. Preferably the mixture having the basic pH is cooled for about 1 to 5 hours, more preferably about 2 to 3 hours. Preferably, the alcohol is C1-alcohol. More preferably, C1-4 alcohol is methanol, ethanol, isopropanol, or butanol and more preferably, ethanol.
Commonly, the compound of formula XIII is hydrolyzed by combining with an acid and heating. Preferably, the acid is an acid mineral, an organic acid, or a mixture thereof. Preferably, the mineral acid is HC1, HBr or sulfuric acid. Preferably, the organic acid is trifluoroacetic acid, acetic acid, formic acid, or propionic acid. More preferably, the acid is mineral acid, and even more preferably, HBr, HC1 or sulfuric acid, and more preferably, either HBr or HC1. Preferably, the acid is in the form of an aqueous solution. More preferably, the organic acid is acetic acid.
Preferably, the combination of the compound of the formula XIII and the acid is heated to a temperature of about 80 ° C to 140 ° C to obtain the 3- isobutylglutaric acid, more preferably about 90 ° C to 130 ° C and more
preferably about 100 ° C to 125 ° C. Preferably, the combination is heated for 12 to 24 hours, more preferably, for 20 to 24 hours.
The 3-isobutylglutaric acid thus obtained can be recovered by cooling the resulting biphasic mixture at a temperature of about 30 ° C to 25 ° C, extracting the 3-isobutylglutaric acid from the mixture with toluene, and extracting the toluene to recover the 3- isobutylglutaric acid. . Preferably, the toluene is extracted by distillation.
Optionally, the process No 3 can be carried out in two steps instead of three, that is, the isovaleraldehyde can be reactivated with approximately two equivalent molecules of the compound of the formula III in a single step. The process comprises (a) combining isovaleraldehyde of the formula I, a compound of the formula III, an alcohol, ammonium acetate, and ammonia to obtain a compound of the formula XIV; and (b) hydrolyzing the compound of formula XIV to obtain 3-isobutylglutaric acid. The process can be illustrated by the following scheme 6.
Characterized in that R2 and R3 are independently H, Ci-8 linear or branched alkyl or C6-i4 aryl. Preferably at least one of R2 and R3 is ethyl.
Preferably, the compound of the formula III is combined with an alcohol, ammonium acetate, the compound of the formula I, and ammonia, at a temperature of about 5 ° C to 20 ° C, more preferably 8 ° C to 10 ° C , to provide a mixture of the reaction. Preferably, the reaction mixture is then maintained at about 30 to 35 minutes. The reaction mixture is then kept at this temperature for about 20 to 60 minutes, preferably about 30 to 35 minutes, followed by heating to a temperature of about 20 ° C to 40 ° C for 20 to 24 hours. Preferably, the reaction mixture was warmed to a temperature of about 25 ° C to 3 ° C. Then, the alcohol was extracted and an acid was added followed by heating with a
temperature of about 80 ° C to 140 ° C for about 2 to 12 hours, preferably 10 to 12 hours.
Preferably, the alcohol is Cl-4 alcohol. More preferably, the Cl-4 alcohol is methanol, ethanol, isopropanol, or butanol, and more preferably methanol.
Commonly, the compound of the formula XIV is hydrolyzed by combining with an acid and heating. Preferably, the acid is a mineral acid, an organic acid or a mixture thereof. Preferably, the mineral acid is HC1 or HBr or sulfuric acid. Preferably, the organic acid is trifluoroacetic acid. More preferably, the acid is a mineral acid, even more preferably HBr, HC1 or sulfuric acid, and more preferably, either HBr or HC1. Preferably, the acid is in the form of an aqueous solution.
Preferably, the combination of the compound of the formula XIV and the acid is heated to a temperature of about 80 ° C to 140 ° C to obtain the 3- isobutylglutaric acid, more preferably at 90 ° C to 130 ° C and more preferably at 100 ° C. ° C to 125 ° C approximately. Preferably, the combination is heated for about 6 to 20 hours, more
preferably for 6 to 16 hours depending on the amount of acid used.
The 3- isobutylglutaric acid thus prepared can be recovered by methods described above.
The 3- isobutylglutaric acid prepared by any of the aforementioned processes can subsequently be converted to (S) -Pregabalin. The conversion can be done, for example, by the process disclosed in U.S. Patent No. 5,616,793 incorporated herein by reference.
The invention further comprises the intermediate compound 3-isobutylglutaric acid of the following formula XIII
Xill
characterized in that R2 and R3 are independently H, Ci_8 linear or branched, or C6-i4 aryl. Preferably, at least one of R2 and R3 is ethyl.
The invention further comprises the intermediate compound of 3-isobutylglutaric acid of the following formula XIV
XIV characterized in that R2 and R3 are independently H, Ci-8 linear or branched, or C6-i4 aryl. Preferably, at least one of R2 and R3 is ethyl.
Having thus described the invention with reference to the particular preferred embodiments, other embodiments will be apparent to the person skilled in the art from the consideration of the specification. The invention is further defined by reference to the following descriptive examples. The examples are set forth to aid in the understanding of the invention but are not intended to limit and should not be considered as a limit of scope. The examples do not include detailed descriptions of conventional methods. It will be evident to experts in the
It is an art that many modifications, both of materials and of methods can be practiced, are to depart from the scope of the invention.
EXAMPLES Example 1. To a four-neck round bottom flask fitted with a mechanical mixer, condenser and charging tube, isovaleraldehyde (1.0 kg, 11.61 molecules), cyclohexane (1.35 L), cycloacetate ethyl (1.28 kg, 11.38 molecules) and di-n-propylamine (11.74 g). The mass of the reaction was heated to reflux and the water was extracted azeotropically. After completing the water extraction (-208 ml), cyclohexane was distilled from the reaction mass followed by small portions of cyclohexane under vacuum. The reaction mass was cooled to 30-35 ° C and diethyl malonate (2.027 kg, 12.67 molecules) was added followed by addition of di-n-propylamine (106.91 g). The mass of the reaction was heated to 50-55 ° C for 3-5 hours and then cooled to 25-30 ° C. Then hydrobromic acid (47%, 23.76 L) was added and the mass was refluxed at 100-125 ° C for 6-10 hours. The reaction mass was cooled to 25-30 ° C and extracted with toluene. The toluene was then distilled to obtain 3- isobutylglutaric acid in a yield of 1.54 kg (71%) having GC purity of 93.59%.
Example 2. To a four-neck round bottom flask fitted with a mechanical mixer, condenser and charging tube, isovaleraldehyde (1.0 kg, 11.61 molecules), cyclohexane (1.35 L), ethyl cyanoacetate was charged. (1.28 kg, 11.38 molecules) and di-n-propylamine (11.74 g). The mass of the reaction was heated to reflux and the water was extracted azeotropically. After completing the water extraction (-208 ml), cyclohexane was distilled from the reaction mass followed by small portions of cyclohexane under vacuum. The reaction mass was cooled to 30-35 ° C and diethyl malonate (2.027 kg, 12.67 molecules) was added followed by addition of di-n-propylamine (106.91 g). The mass of the reaction was heated to 50-55 ° C for 3-5 hours and then cooled to 25-30 ° C. Then a solution of hydrochloric acid (35% hydrochloric acid, 19.79 L in 3.95 L of water) was added and the mass was refluxed at 100-125 ° C for 50-100 hours. The reaction mass was cooled to 25-30 ° C and extracted with toluene. The toluene was then distilled to obtain 3- isobutylglutaric acid in a yield of 1.66 kg (76.14%) having GC purity of 93.64%.
Example 3. To a four-neck round bottom flask adapted with a mechanical mixer, condenser and charging tube, isovaleraldehyde (25 g, 0.290 molecules), cyclohexane (34 ml) was charged,
ethyl cynoacetate (32.19 g, 0.284 molecules) and di-n-propylamine (0.29 g). The mass of the reaction was heated to reflux and the water was extracted azeotropically. After completing the water extraction, cyclohexane was distilled from the reaction mass followed by small portions of cyclohexane under vacuum. The reaction mass was cooled to 30-35 ° C and charged with dimethylsulfoxide (20 ml) followed by the addition of 2,2-dimethyl-1,3-dioxane-4,6-dione (41.86 g, 0.290 g). molecules) and potassium carbonate (19 g, 0.137 molecules). The mass of the reaction was stirred for 1-2 hours at 45-50 ° C. Then hydrochloric acid (6N, 300 ml) was added and the mass was refluxed at a temperature of 100-125 ° C for 15-20 hours. The reaction mass was cooled to 25-30 ° C and extracted with dichloromethane. The dichloromethane was then distilled to obtain 3-isobutylglutaric acid in a yield of 34.4 g (66%) having GC purity of 70.88%.
Example 4. To a four-neck round bottom flask fitted with a mechanical mixer, condenser and charging tube, isovaleraldehyde (10 g, 0.16 molecules), cyclohexane (13.6 ml), 2, 2-dimethyl was charged. -l, 3-dioxane-4,6-dione (22.57 g, 0.156 molecules) and di-n-propylamine (0.2 ml). The mass of the reaction was heated to reflux and the water was extracted azeotropically. After
Complete the extraction of water, cyclohexane was distilled from the reaction mass followed by small portions of cyclohexane under vacuum. The reaction mass was cooled to 30-35 ° C and charged with dimethylsulfoxide (13 ml) followed by addition of 2,2-dimethyl-1,3-dioxane-4,6-dione (41.86 g, 0.290 g). molecules) and potassium carbonate (22.57 g, 0.156 molecules) and potassium carbonate (10.76 g). The reaction mass was stirred for 1-2 hours at 45-50 ° C to obtain the compound of the formula XI. Then HC1 (6N, 300 ml) was added and the mass was refluxed at a temperature of 100-125 ° C for 15-20 hours. The reaction mass was cooled to 25-30 ° C and extracted with dichloromethane. The dichloromethane was then distilled to obtain 3- isobutylglutaric acid in a yield of 14.32 g (65.5%) having GC purity of 75%.
Example 5.? a four-neck round bottom flask adapted with a mechanical mixer, condenser and charging tube, isovaleraldehyde (25 g, 0.290 molecules), cyclohexane (34 ml), diethyl malonate (45.58 g, 0.285 molecules) was charged and di-n-propylamine (0.4 'mi). The mass of the reaction was heated to reflux and the water was extracted azeotropically. After completing the water extraction, cyclohexane was distilled from the reaction mass followed by small portions of cyclohexane under vacuum. The mass of the reaction was cooled to 30-35 ° C and loaded with
dimethylsulfoxide (13 ml) followed by the addition of 2,2-dimethyl-1,3-dioxane-4,6-dione (41.86 g, 0.288 molecules) and potassium carbonate (23.72 g). The reaction mass was stirred for 1-2 hours at 45-50 ° C to obtain the compound of the formula IX. Then HC1 (6N, 650 ml) was added and the mass was refluxed at a temperature of 100-125 ° C for 12-15 hours. The reaction mass was cooled to 25-30 ° C and extracted with dichloromethane. The dichloromethane was then distilled to obtain 3-isobutylglutaric acid in a yield of 34.4 g (63.1%) having GC purity of 90.7%.
Example 6. To a four-neck round bottom flask fitted with a mechanical mixer, condenser and charging tube, isovaleraldehyde (18.85 g, 0.219 molecules), cyclohexane (52 ml), glacial acetic acid (1.24) was charged. ) and diethyl malonate (32.32 g, 0.202 molecules) and di-n-propylamine (1.04 g). The reaction mass was heated to reflux and the water was extracted azeopically. After completing the water extraction, cyclohexane was distilled from the reaction mass followed by small portions of cyclohexane under vacuum. The reaction mass was cooled to 30-35 ° C and charged with dimethyl sulfoxide (25 ml) followed by addition of diethyl malonate (35.0 g, 0.219 molecules) and potassium carbonate (16.67 g). The mass of the reaction
stirred for 4-6 hours at 20-25 ° C to obtain the compound of formula IV. Then HC1 (6N, 400 ml) was added and the mass was refluxed at a temperature of 100-125 ° C for 20-24 hours. The reaction mass was cooled to 25-30 ° C and extracted with toluene. The dichloromethane was then distilled to obtain 3-isobutylglutaric acid in a yield of 27.8 g (67.57%) having GC purity of 93.81%.
Example 7. To a four-neck round bottom flask fitted with a mechanical mixer, condenser and charging tube, isovaleraldehyde (18.85 g, 0.218 molecules), cyclohexane (52 ml), diethyl malonate (32.32) was charged. g, 0.208 molecules) glacial acetic acid (1.24) and di-n-propylamine (1.04 g). The reaction mass was heated to reflux and the water extracted azeotropically. After completing the water extraction, cyclohexane was distilled from the reaction mass followed by small portions of cyclohexane under vacuum. The reaction mass was cooled to 30-35 ° C and charged with dimethylsulfoxide (25 ml) followed by addition of diethyl malonate (35.0 g, 0.218 molecules) and potassium carbonate (16.67 g, 0, 12 molecules) and stirred for 3-4 hours at 25-30 ° C to obtain the compound of formula IV. The mass was cooled to -5o to -10 ° C followed by addition of ethanol (100 ml) and sodium hydroxide solution to raise the
pH to alkaline H The mass was stirred for 2-3 hours at -5 ° C to -10 ° C. The pH of the reaction mass was distilled. After the extraction of ethanol, hydrochloric acid (35%, 1.0 L) was added and the mass was refluxed at a temperature of 100-125 ° C for 20-24 hours. The reaction mass was cooled to 25-30 ° C and extracted with toluene. The dichloromethane was then distilled to obtain 3- isobutylglutaric acid in a yield of 30 g (72.9%) having GC purity of 96.4%.
Example 8. To a four-neck round bottom flask fitted with a mechanical mixer, condenser and charging tube, diethyl malonate (232.8 g, 1.45 molecules) and methanol (50 ml) were charged. The mass of the reaction was cooled to 8-10 ° C followed by addition of isovaleraldehyde (50 g, 0.58 molecules), ammonium acetate (4 g) and aqueous ammonia (25%, 99 g) at 8-10 ° C. The mass of the reaction was stirred for 30-35 minutes at 8-10 ° C by stirring at 25-30 ° C for 20-24 hours. The methanol was then distilled followed by addition of 6N hydrochloric acid (1.5L). The mass of the reaction was refluxed at a temperature of 110-115 ° C for 10-12 hours.1 The reaction mass was cooled to 25-30 ° C and extracted with toluene. The toluene was then distilled to obtain 3-isobutylglutaric acid in a yield of 27.2 g (24.9%) having a GC purity of 60.5%.
Example 9. To a four-neck round bottom flask fitted with a mechanical mixer, condenser and charging tube, isovaleraldehyde (50 g, 0.58 molecules), cyclohexane (67.5 ml), ethyl acetate (64.4 g) was charged. g, 0.57 molecules) and diethyl malonate (100.4 g, 0.62 molecules) and di-n-propylatin (0.76 ml). The mass of the reaction was heated to 40-45 ° C and the water was separated and di-n-propylamine (4.0 ml 0.029 molecules) were added. The reaction mass was heated at 50-55 ° C for 2-5 hours and cyclohexane was distilled from the reaction mass followed by extraction of small portions of cyclohexane in vacuo. The reaction mass was cooled to 30-35 ° C and then hydrobromic acid (47%, 800 ml) was added and the mass was refluxed at 100-125 ° C for 6-10 hours. The reaction mass was cooled to 25-30 ° C and extracted with toluene. The toluene was then distilled to obtain 3-isobutylglutaric acid in a yield of 77.2 g (70%) having a GC purity of 96.06%.
Example 10. To a four-neck round bottom flask fitted with a mechanical mixer, condenser and charging tube, isovaleraldehyde (1.0 kg, 11.61 molecules), cyclohexane (1.35 ml), ethyl acetate (1 g) was charged. , 28 g, 11.38 molecules) and di-n-propylamine (11.74 ml). The mass of the reaction was heated to reflux and the water
It was extracted azeotropically. After completing the extraction of water (), cyclohexane was distilled from the reaction mass followed by extraction of small portions of cyclohexane in vacuo. The reaction mass was cooled to 30-35 ° C and then diethyl malonate (2.027 kg, 12.67 molecules) was added and the thnase was refluxed at 100-125 ° C for 20-25 hours. A portion of the low boiling material was allowed to distill followed by an aqueous solution of hydrochloric acid (35% hydrochloric acid, 1-1.25 L in 1.25 water). The mass was allowed to reflux for 50-10 hours. The reaction mass was cooled to 25-30 ° C and extracted with toluene. The toluene was then distilled to obtain 3- isobutylglutaric acid in a yield of 1.7 kg (79.9%) having a GC purity of 95.2%.
Claims (74)
- A compound of the following formula IX characterized in that R2 and R3 are independently H, C1-8 linear or branched, or C6-14 aryl; and R4 and R5 are independently H, Cx-8 linear or branched, or C6-14 aryl.
- 2. The compound of claim 1, characterized in that at least one of R 2 and R 3 is ethyl and at least one of R 4 and R 5 is methyl.
- 3. A compound of the following formula XII characterized in that R4 and R5 are independently H, Ci-8 linear or branched alkyl or C6-14 aryl.
- 4. The compound of claim 3, characterized in that at least one of R and R5 is methyl.
- 5. A compound of the following formula XIII. XIII characterized in that R2 and R3 are independently H, Ci-8 linear or branched, or C6-i4 aryl.
- 6. The compound of claim 5, characterized in that less one of R2 and R3 is ethyl.
- 7. A compound of the following formula XIV XIV characterized in that R2 and R3 are independently H, Ci-8 linear or branched, or C6-i4 aryl.
- 8. The compound of claim 7, characterized in that at least one of R2 and R3 is ethyl.
- 9. A process for preparing 3- isobutylglutaric acid comprising: (to) . combine isovaleraldehyde, a compound of the following formula II, a compound of the following formula III, III or a compound of the following formula IV, a non-polar organic solvent, and a first base to obtain a compound of the following formula V, a compound of the following formula VIII, IH or a compound of the following formula X, specifically, - (b) combining a compound of formula IV with the compound of formula V, the compound of formula VIII, or the compound of formula X, an aprotic polar organic solvent, and a second base to obtain a compound of the following Formula VII, composed of the following formula XII, respectively, and (c) hydrolyzing the compound of the formula VII, the compound of the formula IX, or the compound of the formula XII to obtain 3- isobutylglutaric acid, characterized in that R is H, Ci-8 linear or branched alkyl or C6-14 aryl; Ri is H, CN, COOH, C00, Ci-8 alkyl, COOC6-i4 aryl or (ReO) 2P = 0; R2 and R3 are independently H, Ci- 8 linear or branched, or C6-i4 aryl; R4 and R5 are independently H, Ci- 8 linear or branched, or C6-i4 aryl; and R6 is 0? -8 linear or branched alkyl or C6-i4 aryl.
- 10. The process of claim 9, characterized in that the process is a process of a container.
- 11. The process of claim 9 or 10, characterized in that at least one of R, R2 and R3 is ethyl.
- 12. The process of any of claims 9 or 11, characterized in that Ri is cyano.
- 13. The process of any of claims 9 to 12, characterized in that at least one of R4 and R5 is methyl.
- 14. The process of any of claims 9 to 13 characterized in that R6 is methyl, ethyl or phenyl.
- 15. The process of any of claims 9 to 14, characterized in that the non-polar organic solvent is selected from Cé-9 linear, branched or cyclic hydrocarbons and C6.9 aromatic hydrocarbons.
- 16. The process of claim 15, characterized in that the linear, branched or cyclic hydrocarbon C6-9 is hexane, heptane or cyclohexane.
- 17. The process of claim 15, characterized the C6-9 aromatic hydrocarbons is toluene.
- 18. The process of any of claims 9 to 17 characterized in that the first base is an organic base.
- 19. The process of claim 18, characterized in that the organic base is di-n-propylamine, triethylamine, piperidine or diisopropylamine.
- 20. The process of any of claims 9 to 19, characterized in that the second base is an inorganic base.
- 21. The process of claim 20, characterized in that the inorganic base is potassium carbonate, sodium cesium carbonate carbonate.
- 22. The process of any of claims 9 to 21 characterized in that the polar aprotic organic solvent is dimethylsulfoxide, N-N-dimethylformamide, or dimethylacetamide.
- 23. The process of any of claims 9 to 22 characterized in that the combination of step (a) is heated and the water is extracted azeotropically during the course of the reaction to promote the formation of the compound of formula V, the compound of Formula VIII, or the compound of the formula X.
- 24. The process of claim 23, characterized by, after extraction of the water, the non-polar organic solvent is extracted to obtain a concentrated mixture having the compound of the formula V, the compound of the formula VIII or the compound of the formula X.
- 25. The process of claim 24, characterized in that the concentrated mixture is cooled before combining with the polar aprotic organic solvent and the second base.
- 26. The process of any of claims 9 to 25 characterized in that the combination of step (b) is heated to obtain the compound of the formula VII, the compound of the formula IX or the compound of the formula XII.
- 27. The process of any of claims 9 to 26 characterized in that the compound of the formula VII, the compound of the formula IX, or the compound of the formula XII is hydrolyzed by combining with an acid and heating.
- 28. The process of claim 27, characterized in that the acid is a mineral acid, an organic acid or a mixture thereof.
- 29. The process of claim 28, characterized in that the mineral acid is HC1, HBr or sulfuric acid.
- 30. The process of claim 28, characterized in that the organic acid is trifluoroacetic acid.
- 31. The process of claim 27, characterized in that the combination of the compound of the formula VII, the compound of the formula IX, or the compound of the formula XII and the acid is heated to a temperature of about 80 ° C to about 140 ° C. . ,
- 32. A process for preparing (S) -pregabalin comprising: (a) prepare 3- isobutylglutaric acid by the process of any of claims 9 to 31; and (b) converting 3-isobutylglutaric acid to (S) -pregabalin.
- 33. A process for preparing 3- isobutylglutaric acid comprising: (a) combine isovaleraldehyde, a compound of the following formula III, OR, OR, III a non-polar organic solvent, an organic acid, and an organic base to obtain a compound of the following formula VIII; VIII (b) combining the compound of the formula VIII with the compound of the formula III, a polar aprotic organic solvent and an inorganic base to obtain a compound of the following formula XIII; Y XIII (c) hydrolyzing the compound of formula XIII to obtain 3- isobutylglutaric acid, characterized in that R2 and R3 are independently H, Ci-8 linear or branched, or C6-i4 aryl.
- 34. The process of claim 33, characterized in that the process is a process of a container.
- 35. The process of claim 33 or 34, characterized in that at least one of R2 and R3 is ethyl.
- 36. The process of claim 33 or 35, characterized in that the non-polar organic solvent is selected from C6.9 linear, branched or cyclic hydrocarbons and C6_9 aromatic hydrocarbons
- 37. The process of claim 36 characterized in that the linear, branched or cyclic hydrocarbon C6-9 is hexane, heptane or cyclohexane.
- 38. The process of claim 36 characterized in that C6-9 aromatic hydrocarbon is toluene.
- 39. The process of any of claims 33 to 38 characterized in that the organic base is di-n-propylamine, triethylamine, piperidine or diisopropylamine.
- 40. The process of any of claims 33 to 39 characterized in that the inorganic base is potassium carbonate, cesium carbonate or sodium carbonate.
- 41. The process of any of claims 33 to 40 characterized in that the polar aprotic organic solvent is dimethyl sulfoxide, N-N-dimethylformamide or dimethylacetamide.
- 42. The process of any of claims 33 to 41 characterized by the combination of step (a) is heated and the water is extracted azeotropically during the course of the reaction to promote the formation of the compound of formula VIII.
- 43. The process of claim 42, characterized in that, after extraction of water, the non-polar organic solvent is extracted to obtain a concentrated mixture having the compound of formula VIII.
- 44. The process of claim 43, characterized in that the concentrated mixture was cooled before combining with the aprotic organic solvent, the compound of the formula III and the inorganic base.
- 45. The process of any of claims 33 to 44 characterized by the combination of step (b) is heated to obtain the compound of the formula XIII.
- 46. The process of any of claims 33 to 45, further comprises prior to hydrolysis, cooling the compound of formula XIII; (ii) combining the compound of the formula XIII with an alcohol and sodium hydroxide to obtain a mixture having a basic pH; (iii) cooling the mixture; (iv) combining the mixture with glacial acetic acid and HC1 to obtain a mixture having an acidic pH; and (v) extract the alcohol.
- 47. The process of claim 46 characterized in that the compound of the formula XIII is cooled to a temperature of about -5 ° C to about -20 ° C.
- 48. The process of claim 46 or 47 characterized in that the basic pH is about 7 to 10.
- 49. The process of any of claims 46 to 48 characterized in that the pH is from about 3 to 6.
- 50. The process of any of claims 46 to 49 characterized in that the alcohol is Ci-4 alcohol.
- 51. The process of claim 50, characterized in that Ci-4 alcohol is methanol, ethanol, isopropanol or butanol.
- 52. The process of any of claims 33 to 51 characterized in that the compound of the formula XIII is hydrolyzed by combining with an acid and heating.
- 53. The process of claim 52 characterized in that the acid is a mineral acid, an organic acid or a mixture thereof.
- 54. The process of claim 53 characterized in that mineral acid1 is HC1, HBr, or sulfuric acid.
- 55. The process of claim 53, characterized in that the organic acid is trifluoroacetic acid, acetic acid, formic acid, or propionic acid.
- 56. The process of claim 53 or 55 characterized in that the organic acid is acetic acid.
- 57. The process of any of claims 52 to 56 characterized in that the combination of the compound of the formula XIII and the acid is heated to a temperature of about 80 ° C to 140 ° C.
- 58. A process for preparing (S) -pregabalin comprising: (a) preparing 3- isobutylglutaric acid by the process of any of claims 33 to 57; Y (b) converting 3-isobutylglutaric acid to (S) -pregabalin.
- 59. A process for preparing 3- isobutylglutaric acid comprising: (a) combine isovaleraldehyde, a compound of the following formula III, III an alcohol, ammonium acetate and ammonia to obtain a compound of the following formula XIV; XIV Y (b) hydrolyzing the compound of formula XIV to obtain 3- isobutylglutaric acid, characterized in that R2 and 3 are independently H, Ci-8 linear or branched, or C6-aryl.
- 60. The process of claim 59, characterized in that the process is a process of a container.
- 61. The process of claim 59 or 60 characterized in that at least one of R2 and 3 is ethyl.
- 62. The process of any of claims 59 to 61 characterized in that the isovaleraldehyde, the compound of the formula III, the alcohol, the ammonium acetate, and the ammonia are combined at a temperature of about 5 ° C to 20 ° C.
- 63. The process of claim 62 characterized in that the combination of step (a) is maintained at a temperature of about 5 ° C to 20 ° C for about 20 to 60 minutes.
- 64. The process of any of claims 62 or 63 characterized in that the combination of step (a) is subsequently warmed to a temperature of about 20 ° C to 40 ° C.
- 65. The process of claim 64, characterized in that the alcohol is extracted before step (b).
- 66. The process of any of claims 59 to 65 characterized in that the alcohol is C1-4 alcohol.
- 67. The process of any of claims 59 to 66 characterized in that the alcohol is methanol, ethanol, isopropanol or butanol.
- 68. The process of any of claims 59 to 66 characterized in that the compound of the formula XIV is hydrolyzed by combining with an acid and heating.
- 69. The process of claim 68, characterized in that the acid is a mineral acid, an organic acid, or a mixture thereof.
- 70. The process of claim 69, characterized in that the mineral acid is HC1, HBr, or sulfuric acid.
- 71. The process of any of claims 68 to 70 characterized in that the combination of the compound of the formula XIV and the acid is heated to a temperature of about 80 ° C to 140 ° C.
- 72. A process for preparing (S) -pregabalin comprising: (a) preparing 3- isobutylglutaric acid by the process of any of claims 59 to 71; and (b) converting 3-isobutylglutaric acid to (S) -pregabalin.
- 73. A process for preparing 3- isobutylglutaric acid comprising: (a) combine isovaleraldehyde, a compound of formula II, II a non-polar organic solvent, and a first base to obtain a compound of the following formula V; V (b) combining the compound of the formula V with a compound of the following formula III OR3 OR, and a second base to obtain a compound of the following formula VI SAW (c) combining the compound of the formula VI with an acid and heating to obtain 3- isobutylglutaric acid, characterized in that R is H, C1-8 linear or branched alkyl or C6-i4 aryl; Rx is H, CN, COOH, C00, Ci-8 alkyl, COOC6-i4 aryl or (R60) 2P = 0; R2 and R3 are independently H, linear or branched Ci-8, or Ce-14 aryl; and R6 is C1-8 linear or branched alkyl or C6-i4 aryl.
- 74. Use of a compound of formula IX, XII, XIII or XIV as defined in any of claims 1 to 8 in a process for the manufacture of (S) -pregabalin.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/794,818 | 2006-04-24 | ||
US60/802,620 | 2006-05-22 |
Publications (1)
Publication Number | Publication Date |
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MX2007015724A true MX2007015724A (en) | 2008-10-03 |
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