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148553-50-8

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148553-50-8 Usage

Description

Pregabalin, marketed as the anticonvulsant drug Lyrica, is a second-generation antiepileptic drug (AED) and a GABA analogue. It is used in the treatment of epilepsy, generalized anxiety disorder, neuropathic pain, and fibromyalgia. Pregabalin is known for its more selective action on the a2-δ subunit of calcium channels found in the brain compared to gabapentin. It is an anxiolytic analgesic and has a potential for abuse and misuse, being regulated as a Schedule V compound in the United States.

Uses

Used in Pharmaceutical Industry:
Pregabalin is used as an anticonvulsant for the treatment of epilepsy and partial seizures. It helps in controlling the frequency and severity of seizures, providing relief to patients suffering from this neurological disorder.
Pregabalin is used as an anxiolytic for the treatment of generalized anxiety disorder. It helps in reducing anxiety levels and improving the overall quality of life for patients dealing with this mental health condition.
Pregabalin is used as an analgesic for the treatment of neuropathic pain, which is a type of chronic pain caused by nerve damage. It is particularly effective in managing peripheral neuropathic pain and fibromyalgia, providing relief to patients suffering from these conditions.
Pregabalin is used as an adjunct therapy for partial seizures, enhancing the effectiveness of other anticonvulsant medications and improving the management of seizure disorders.
In addition to its medical applications, Pregabalin is also used in forensic analysis, clinical toxicology, and pain prescription monitoring, as well as urine drug testing, due to its certified reference standard status.

Generic formulation

MHRA/ CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (including generic products): It is usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific concerns, such as patient anxiety and risk of confusion/ dosing error.

Indications

Epilepsy Adjunctive therapy of focal seizures with and without secondary generalization. Recommendations summarized from NICE (2012) Seizure types—on referral to tertiary care (focal seizures), contraindicated (generalized tonic- clonic seizures, tonic/ atonic seizures, absence seizures, myoclonic seizures). Epilepsy types—on referral to tertiary care (benign epilepsy with centrotemporal spikes, panayiotopoulos syndrome, late- onset childhood occipital epilepsy), contraindicated (absence syndromes, idiopathic generalized epilepsy, juvenile myoclonic epilepsy, Dravet syndrome, Lennox– Gastaut syndrome). Psychiatry Generalized anxiety disorder. Neurology Peripheral and central neuropathic pain.

Dose titration

Epilepsy— adjunctive therapy: 25 mg bd for 7 days, to be increased by 50 mg every 7days; usual maintenance 300 mg daily, divided into 2 or 3 doses (max. 600 mg daily, divided into 2 or 3 doses). Generalized anxiety disorder: 150 mg daily, divided into 2 or 3 doses, for 7 days, to be increased by 150 mg every 7 days (max. 600 mg daily, divided into 2 or 3 doses). If stopping pregabalin, it is recommended to taper over at least 1?week to avoid abrupt withdrawal.

Plasma levels monitoring

Pregabalin pharmacokinetics are linear over the recommended daily dose range; inter- subject pharmacokinetic variability for pregabalin is low (<20%) and multiple dose pharmacokinetics are predictable from single- dose data. Therefore, there is no need for routine monitoring of plasma concentrations of pregabalin.

Antiepileptic drus and therapeutic drugs for neuropathic pain

Pregabalin is a new antiepileptic drug, having a γ-amino butyric acid structure on its molecular structure, which has anticonvulsant effects, and is successfully developed by the company Pfizer for the treatment of peripheral neuropathic pain, or adjuvant treatment of partial seizures. In December 2008, the US Food and Drug Administration (FDA) approved pregabalin (trade name "Lyrica") for the treatment of diabetic peripheral neuropathic pain (DPN) and postherpetic neuralgia (PHN)which are Both the most common neuropathic pains. Neuropathic pain is one of the most difficult chronic pain syndromes to treat , dull pain, burning, tingling as the main feature, there are a lot of incentives of neuralgia, diabetes, infections (such as herpes zoster), cancer and AIDS, etc. can cause neurological pain, in Europe about 3% of the population suffer from neuralgia torture. The above information is edited by the lookchem of Tian Ye.

Cautions

Patients with conditions that may precipitate encephalopathy. Patients with severe congestive heart failure.

Adverse effects

Pregabalin can be associated with adverse effects at the level of the nervous system and other systems.

Interactions

Since pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans, does not inhibit drug metabolism in vitro, and is not bound to plasma proteins, it is unlikely to produce or be subject to pharmacokinetic interactions. Pregabalin may potentiate the effects of lorazepam. In the post- marketing experience, there are reports of respiratory failure and coma in patients taking pregabalin and other central nervous system depressant medicinal products. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone. With alcohol/food There are no specific foods that must be excluded from diet when taking pregabalin. Pregabalin may potentiate the effects of alcohol.

Special populations

Hepatic impairment No dose adjustment is required for patients with hepatic impairment. Renal impairment Reduce maintenance dose according to degree of reduction in creatinine clearance. Pregnancy There is no adequate data from the use of pregabalin in pregnant women. The potential risk for reproductive toxicity in humans is unknown. Pregabalin should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus. Pregabalin is excreted into human milk. The effect of pregabalin on newborns/ infants is unknown. A case- by- case decision must be made whether to discontinue breast- feeding or to discontinue pregabalin therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Behavioural and cognitive effects in patients with epilepsy

Pregalin is characterized by a good behavioural profile. This AED does not appear to have significant negative effects on mood or behaviour in patients with epilepsy, although depression has been reported in some patients (dose- dependent effects of mild- to- moderate intensity). A potential abuse or misuse of pregabalin has also been reported, with implications in terms of dependence and withdrawal. pregabalin is also associated with limited negative cognitive effects, mainly related to sedation, decreased arousal, decreased attention and concentration (dose- dependent effects of mild- to- moderate intensity).

Psychiatric use

Pregabalin has an approved indication and is widely used for the treatment of generalized anxiety disorder. Several randomized, double- blind, placebocontrolled trials found that pregabalin is an effective treatment for patients with generalized anxiety disorder and social anxiety disorder. Possible implications in the treatment of mood disorders and benzodiazepines dependence are emerging. Moreover, pregabalin may be a therapeutic agent for the treatment of alcohol abuse, in both withdrawal phase and relapse prevention.

Originator

Warner-Lambert (US)

Biochem/physiol Actions

Pregabalin is a lipophilic GABA analog/ligand at α2δ subunit of voltage-dependent Ca2+ channels. Pregabalin is an anticonvulsant, anxiolytic analgesic used to treat peripheral neuropathic pain and fibromyalgia.

Clinical Use

Antiepileptic Neuropathic pain Generalised anxiety disorder

Synthesis

Several syntheses of pregabalin (X) have been disclosed in the literature, including process scale-up comparison of several different routes. The most cost efficient route as described in the publication is shown in the Scheme. Condensation of diethyl malonate 69 in the presense of diisopropyl amine in acetic acid gave a,b-unsaturated diester 70 in high yield. Reaction of the enone diester with potassium cyanide gave cyano diester 71 in 95% yield. In a remarkable three step, one pot process, the nitrile in 71 was hydrolyzed followed by decarboxylation of one of the esters to provide 72 in 73% yield. Resolution of the two enantiomers was achieved using (S)-(+)-mandellic acid, one of the best acid found after many salt screening, to give, after two recrystallization, a 99:1 ratio of the desired diastereomer.Removal of the acid was done with wet THF instead of base separation, to avoid salt impurities, and one recrystallization in ethanol gave 100% ee diastereomer in 25 – 29% overall yield.It’s worth noting that the Pfizer group have come up with a new process of preparing pregabalin (X) via enantioselective reduction, that promises to further reduce cost and waste associated with the manufacture of this drug.

Drug interactions

Potentially hazardous interactions with other drugs Antidepressants: anticonvulsant effect antagonised. Antimalarials: anticonvulsant effect antagonised by mefloquine. Antipsychotics: anticonvulsant effect antagonised. Orlistat: possible increased risk of convulsions.

Metabolism

Pregabalin undergoes negligible metabolism, and about 98% of a dose is excreted in the urine as unchanged drug.

Check Digit Verification of cas no

The CAS Registry Mumber 148553-50-8 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,8,5,5 and 3 respectively; the second part has 2 digits, 5 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 148553-50:
(8*1)+(7*4)+(6*8)+(5*5)+(4*5)+(3*3)+(2*5)+(1*0)=148
148 % 10 = 8
So 148553-50-8 is a valid CAS Registry Number.
InChI:InChI=1/C8H17NO2/c1-6(2)3-7(5-9)4-8(10)11/h6-7H,3-5,9H2,1-2H3,(H,10,11)/t7-/m0/s1

148553-50-8 Well-known Company Product Price

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  • (Y0001805)  Pregabalin  EuropePharmacopoeia (EP) Reference Standard

  • 148553-50-8

  • Y0001805

  • 1,880.19CNY

  • Detail

148553-50-8SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 20, 2017

Revision Date: Aug 20, 2017

1.Identification

1.1 GHS Product identifier

Product name pregabalin

1.2 Other means of identification

Product number -
Other names (S)-3-(Aminomethyl)-5-methylhexanoic acid CI-1008 PD-144723

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:148553-50-8 SDS

148553-50-8Synthetic route

(R)-3-((tert-butoxycarbonylamino)methyl)-5-methylhex-4-enoic acid
1021167-91-8

(R)-3-((tert-butoxycarbonylamino)methyl)-5-methylhex-4-enoic acid

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With hydrogenchloride; hydrogen; palladium dihydroxide In methanol at 20℃; under 4560.31 Torr;100%
(S)-3-azidomethyl-5-methylhexanoic acid
157422-27-0

(S)-3-azidomethyl-5-methylhexanoic acid

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With hydrogen; palladium on activated charcoal In methanol for 3h;99%
With hydrogen; palladium 10% on activated carbon In methanol for 3h;99%
palladium on activated charcoal In tert-butyl methyl ether59%
palladium on activated charcoal In tert-butyl methyl ether59%
(S)-3-azidomethyl-5-methyl-hexanoic acid ethyl ester
951792-40-8

(S)-3-azidomethyl-5-methyl-hexanoic acid ethyl ester

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With hydrogen; palladium 10% on activated carbon In methanol for 3h;99%
Multi-step reaction with 2 steps
1: 90.9 percent / LiOH*H2O / tetrahydrofuran; methanol; H2O / 0.25 h / Heating
2: 99 percent / H2 / Pd/C / methanol / 3 h
View Scheme
C23H29NO4
1253690-87-7

C23H29NO4

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; under 7500.75 Torr; for 15h;99%
(3R)‐3‐(carbamoylmethyl)‐5‐methylhexanoic acid
181289-33-8

(3R)‐3‐(carbamoylmethyl)‐5‐methylhexanoic acid

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
Stage #1: (3R)‐3‐(carbamoylmethyl)‐5‐methylhexanoic acid With sodium hydroxide In water at 0 - 10℃; for 0.166667h; Hofmann Rearrangement; Large scale;
Stage #2: With sodium hypochlorite In water at 0 - 75℃; for 1h; Temperature; Hofmann Rearrangement; Large scale;
97.7%
Stage #1: (3R)‐3‐(carbamoylmethyl)‐5‐methylhexanoic acid With sodium hypochlorite; sodium hydroxide In water at -15 - -10℃; for 3h; Industrial scale;
Stage #2: With sodium sulfite at -10 - 40℃; for 5h; Reagent/catalyst; Temperature; Industrial scale; Further stages;
85%
With sodium hypochlorite; sodium hydroxide In water at 10 - 47℃; Temperature;83%
5-methyl-3-(nitromethyl)hexanoic acid
181289-21-4

5-methyl-3-(nitromethyl)hexanoic acid

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 24h; Reagent/catalyst; Solvent; Time; Temperature;96%
With palladium on activated charcoal; hydrogen In methanol; water at 20℃; under 2660.18 - 3040.2 Torr; for 16h;
(S)-(+)-5-methyl-3-(nitromethyl)hexanoic acid
181289-45-2

(S)-(+)-5-methyl-3-(nitromethyl)hexanoic acid

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With hydrogen In methanol; water at 18℃;95%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; under 760.051 Torr; Solvent;77%
With hydrogen; 5%-palladium/activated carbon In methanol for 5 - 8h;35%
With hydrogen; 5% Pd(II)/C(eggshell) In methanol35%
With hydrogen; palladium on activated charcoal In methanol at 20℃; for 48h;
(S)-3-(aminomethyl)-5-methyl-N-((S)-1-phenylethyl)hexanamide
1310495-04-5

(S)-3-(aminomethyl)-5-methyl-N-((S)-1-phenylethyl)hexanamide

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With sodium hydroxide In tetrahydrofuran; water at 65℃; for 6h; Reagent/catalyst;95%
Stage #1: (S)-3-(aminomethyl)-5-methyl-N-((S)-1-phenylethyl)hexanamide With water; hydrogen bromide at 100 - 110℃; for 5h;
Stage #2: With sodium hydroxide In water
83%
C10H17NO3

C10H17NO3

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
Stage #1: C10H17NO3 With hydrogenchloride In water for 24h; Reflux;
Stage #2: With sodium hydroxide In water pH=7.2;
95%
sodium 5-methyl-3-nitromethyl-hexanoate

sodium 5-methyl-3-nitromethyl-hexanoate

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With hydrogen In methanol at 20℃; under 760.051 Torr; for 6h; Reagent/catalyst;95%
(S)-4-isobutyl-pyrrolidin-2-one
181289-23-6

(S)-4-isobutyl-pyrrolidin-2-one

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With ethanol; sodium hydroxide at 40℃; for 5h; Green chemistry;94.1%
With lipase from Rhizopus delemar; sodium carbonate In water at 35℃; for 5h; pH=9 - 10; Reagent/catalyst; Solvent; Temperature; Enzymatic reaction;93.2%
With hydrogenchloride In water at 100 - 106℃; for 10h;88%
(S)-pregabalin-(-)-O,O'-dibenzoyl-L-tartrate
1078737-39-9

(S)-pregabalin-(-)-O,O'-dibenzoyl-L-tartrate

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With ammonia In methanol; water at 0℃;93%
{(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)methyl]pentyl}carbamic acid methyl ester
930280-44-7

{(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)methyl]pentyl}carbamic acid methyl ester

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
Stage #1: {(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)methyl]pentyl}carbamic acid methyl ester With hydrogen bromide In water for 3h; Heating / reflux;
Stage #2: With sodium hydroxide In water at 20℃; pH=3;
Stage #3: With tributyl-amine In 2-methyl-propan-1-ol at 2℃; for 1h; Product distribution / selectivity;
90%
Stage #1: {(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)methyl]pentyl}carbamic acid methyl ester With sulfuric acid In water at 115 - 120℃; for 5 - 10h;
Stage #2: With sodium hydroxide In water at 20 - 25℃; pH=1;
Stage #3: With tributyl-amine In 2-methyl-propan-1-ol pH=4; Product distribution / selectivity;
40.4%
Stage #1: {(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)methyl]pentyl}carbamic acid methyl ester With hydrogenchloride; sodium chloride; phenol In water at 105 - 110℃; for 15 - 24h;
Stage #2: With sodium hydroxide In water at 20 - 25℃; pH=1;
Stage #3: With tributyl-amine In 2-methyl-propan-1-ol pH=4 - 4.5; Product distribution / selectivity;
Stage #1: {(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)methyl]pentyl}carbamic acid methyl ester With hydrogenchloride; sodium chloride; phenol In methanol; water at 105 - 110℃; for 15 - 24h;
Stage #2: With sodium hydroxide In methanol; water at 20 - 25℃; pH=1;
Stage #3: With tributyl-amine In 2-methyl-propan-1-ol pH=4 - 5; Product distribution / selectivity;
(S)-3-(isopropoxycarbonyl-aminomethyl)-5-methyl-hexanoic acid (S)-(-)-1-phenylethylamine salt
1082077-26-6

(S)-3-(isopropoxycarbonyl-aminomethyl)-5-methyl-hexanoic acid (S)-(-)-1-phenylethylamine salt

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
Stage #1: (S)-3-(isopropoxycarbonylamino-methyl)-5-methyl-hexanoic acid (S)-(-)-1-phenylethylamine salt With hydrogenchloride In water; toluene for 0.166667 - 0.25h;
Stage #2: With hydrogenchloride; water at 90℃; for 24 - 48h;
Stage #3: With methylamine In water pH=~ 6;
88%
Stage #1: (S)-3-(isopropoxycarbonylamino-methyl)-5-methyl-hexanoic acid (S)-(-)-1-phenylethylamine salt With hydrogenchloride In water at 90℃; Inert atmosphere;
Stage #2: With methylamine In water; toluene at 0 - 90℃; for 1h; pH=6;
88%
Stage #1: (S)-3-(isopropoxycarbonylamino-methyl)-5-methyl-hexanoic acid (S)-(-)-1-phenylethylamine salt With hydrogenchloride; water at 90 - 95℃; for 24h;
Stage #2: With sodium hydroxide; water at 0 - 5℃; for 1h; Product distribution / selectivity;
82%
isopropyl (S)-{4-methyl-2-[(1-methoxycarbonyl)methyl]pentyl}-carbamate
1082077-19-7

isopropyl (S)-{4-methyl-2-[(1-methoxycarbonyl)methyl]pentyl}-carbamate

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
Stage #1: isopropyl (S)-{4-methyl-2-[(1-methoxycarbonyl)methyl]pentyl}-carbamate With hydrogenchloride; water at 90℃; for 24 - 48h;
Stage #2: With water; methylamine pH=~ 6; Product distribution / selectivity;
88%
(S)-(+)-pregabalin (2R,3R)-(+)-tartaric acid

(S)-(+)-pregabalin (2R,3R)-(+)-tartaric acid

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With N-ethyl-N,N-diisopropylamine In water; isopropyl alcohol at 20 - 25℃; pH=7.0 - 7.5; Product distribution / selectivity;88%
With ammonium hydroxide In water at 0 - 65℃; Product distribution / selectivity;81.1%
(S)-pregabalin O,O'-di-p-toluoyl-(D)-tartrate

(S)-pregabalin O,O'-di-p-toluoyl-(D)-tartrate

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With N-ethyl-N,N-diisopropylamine In water; isopropyl alcohol at 20 - 25℃; pH=7.0 - 7.5;87%
(S)-3-bromomethyl-5-methyl-hexanoic acid ethyl ester
951792-39-5

(S)-3-bromomethyl-5-methyl-hexanoic acid ethyl ester

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
Stage #1: (S)-3-bromomethyl-5-methyl-hexanoic acid ethyl ester With sodium azide In N,N-dimethyl-formamide at 20℃; for 5h;
Stage #2: With 5%-palladium/activated carbon; hydrogen at 20℃; for 5h;
84.5%
Multi-step reaction with 3 steps
1: 92.9 percent / NaN3 / dimethylformamide / 4 h / 20 °C
2: 90.9 percent / LiOH*H2O / tetrahydrofuran; methanol; H2O / 0.25 h / Heating
3: 99 percent / H2 / Pd/C / methanol / 3 h
View Scheme
C8H8O3*C8H17NO2
1026095-29-3

C8H8O3*C8H17NO2

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
In tetrahydrofuran; water at 0 - 55℃; for 5h;83%
(S)-3-[(dibenzylamino)methyl]-5-methylhexanoic acid

(S)-3-[(dibenzylamino)methyl]-5-methylhexanoic acid

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; under 3750.38 Torr; for 24h; Solvent; Pressure;82.7%
C13H25NO4

C13H25NO4

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With water; sodium hydroxide at 24℃; Reflux;81%
(S)-4-isobutyl-2-oxo-pyrrolidine-3-carboxylic acid

(S)-4-isobutyl-2-oxo-pyrrolidine-3-carboxylic acid

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
Stage #1: (S)-4-isobutyl-2-oxo-pyrrolidine-3-carboxylic acid With hydrogenchloride; water In ethyl acetate at 80 - 110℃; for 42 - 44h;
Stage #2: With potassium hydroxide In water pH=5.2 - 5.5;
80%
C13H24N2O2

C13H24N2O2

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With hydrogenchloride In water for 36h; Reflux;80%
C21H26N2O3

C21H26N2O3

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With perchloric acid; water for 12h; Reflux;79%
C16H29NO6

C16H29NO6

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With hydrogenchloride In water for 72h; Reflux;79%
C17H25NO4

C17H25NO4

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With water; potassium hydroxide In water for 20h; Reflux;78%
methyl (S)-3-cyano-5-methyl-hexanoate

methyl (S)-3-cyano-5-methyl-hexanoate

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
Stage #1: methyl (S)-3-cyano-5-methyl-hexanoate With water; potassium hydroxide In methanol at 20 - 25℃; for 1.5h;
Stage #2: With hydrogen In methanol at 30℃; under 7500.75 Torr; for 48h; Reagent/catalyst; Temperature; Time;
74.62%
Multi-step reaction with 2 steps
1: nickel dichloride; sodium tetrahydroborate; methanol
2: hydrogenchloride; water
View Scheme
(-)-(S)-3-(benzyloxycarbonylamino-methyl)-5-methyl-hexanoic acid
949890-75-9

(-)-(S)-3-(benzyloxycarbonylamino-methyl)-5-methyl-hexanoic acid

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With palladium on activated charcoal; hydrogen In methanol at 40℃; under 11251.1 Torr; for 10h; Solvent;68%
With hydrogen; palladium on activated charcoal In methanol at 20℃; under 7500.75 Torr; for 15h;60%
With palladium on activated charcoal; hydrogen In methanol at 20℃; under 11251.1 Torr; for 15h;60%
3-(azidomethyl)-5-methyl-hexanoic acid phenylmethyl ester
156048-97-4

3-(azidomethyl)-5-methyl-hexanoic acid phenylmethyl ester

pregabilin
148553-50-8

pregabilin

Conditions
ConditionsYield
With hydrogenchloride; palladium on activated charcoal In tetrahydrofuran; water at 20℃;65%
(1R)-1-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)ethyl 2-methylpropionate
1174524-47-0

(1R)-1-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)ethyl 2-methylpropionate

pregabilin
148553-50-8

pregabilin

3-{[(α-(R)-isobutanoyloxyethoxy)carbonyl]aminomethyl}-5-(S)-methylhexanoic acid
1174748-30-1

3-{[(α-(R)-isobutanoyloxyethoxy)carbonyl]aminomethyl}-5-(S)-methylhexanoic acid

Conditions
ConditionsYield
In water; acetonitrile at 20℃; for 16h;100%
(S)-1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanate
1174524-50-5

(S)-1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanate

pregabilin
148553-50-8

pregabilin

3-{[(α-(S)-isobutanoyloxyisobutoxy)carbonyl]aminomethyl}-5-(S)-methylhexanoic acid
1179336-90-3

3-{[(α-(S)-isobutanoyloxyisobutoxy)carbonyl]aminomethyl}-5-(S)-methylhexanoic acid

Conditions
ConditionsYield
In water; acetonitrile at 20℃; for 6h;100%
{[(1R)-Benzoyloxyethoxy]carbonyloxy}succinimide
1174524-53-8

{[(1R)-Benzoyloxyethoxy]carbonyloxy}succinimide

pregabilin
148553-50-8

pregabilin

(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoic acid
1174748-47-0

(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoic acid

Conditions
ConditionsYield
In water; acetonitrile at 20℃; for 16h;100%
lauric acid
143-07-7

lauric acid

pregabilin
148553-50-8

pregabilin

(S)-3-(aminomethyl)-5-methylhexanoic acid laurate
1414928-47-4

(S)-3-(aminomethyl)-5-methylhexanoic acid laurate

Conditions
ConditionsYield
In isopropyl alcohol for 1.5h; Product distribution / selectivity;100%
maleic acid
110-16-7

maleic acid

pregabilin
148553-50-8

pregabilin

(S)-3-(aminomethyl)-5-methylhexanoic acid maleate
1414928-41-8

(S)-3-(aminomethyl)-5-methylhexanoic acid maleate

Conditions
ConditionsYield
In 2-methylpropyl acetate for 0.75h; Product distribution / selectivity;100%
benzoic acid
65-85-0

benzoic acid

pregabilin
148553-50-8

pregabilin

(S)-3-(aminomethyl)-5-methylhexanoic acid benzoate
1414928-43-0

(S)-3-(aminomethyl)-5-methylhexanoic acid benzoate

Conditions
ConditionsYield
for 0.75h; Product distribution / selectivity;100%
Octanoic acid
124-07-2

Octanoic acid

pregabilin
148553-50-8

pregabilin

(S)-3-(aminomethyl)-5-methylhexanoic acid caprylate
1414928-45-2

(S)-3-(aminomethyl)-5-methylhexanoic acid caprylate

Conditions
ConditionsYield
In tert-butyl methyl ether for 0.75h;100%
1-decanoic acid
334-48-5

1-decanoic acid

pregabilin
148553-50-8

pregabilin

(S)-3-(aminomethyl)-5-methylhexanoic acid caprate
1414928-46-3

(S)-3-(aminomethyl)-5-methylhexanoic acid caprate

Conditions
ConditionsYield
In tert-butyl methyl ether for 0.75h;100%
di-tert-butyl dicarbonate
24424-99-5

di-tert-butyl dicarbonate

pregabilin
148553-50-8

pregabilin

3-((tert-butoxycarbonylamino)methyl)-5-methylhexanoic acid
228104-41-4

3-((tert-butoxycarbonylamino)methyl)-5-methylhexanoic acid

Conditions
ConditionsYield
With sodium hydroxide In 1,4-dioxane; water98%
pregabilin
148553-50-8

pregabilin

(S)-4-isobutyl-pyrrolidin-2-one
181289-23-6

(S)-4-isobutyl-pyrrolidin-2-one

Conditions
ConditionsYield
With acidic kaolin In 5,5-dimethyl-1,3-cyclohexadiene for 6h; Solvent; Reagent/catalyst; Reflux;97%
With diazomethyl-trimethyl-silane In methanol; hexane for 0.5h;
at 80℃; for 336h; Kinetics; Temperature;
L-mandelate anion

L-mandelate anion

pregabilin
148553-50-8

pregabilin

(S)-Mandelic acid
17199-29-0

(S)-Mandelic acid

Conditions
ConditionsYield
With pyrographite In isopropyl alcohol at 0 - 85℃; for 4h;95%
di-tert-butyl dicarbonate
24424-99-5

di-tert-butyl dicarbonate

pregabilin
148553-50-8

pregabilin

(S)-3-(((tert-butoxycarbonyl)amino)methyl)-5-methylhexanoic acid
649748-09-4

(S)-3-(((tert-butoxycarbonyl)amino)methyl)-5-methylhexanoic acid

Conditions
ConditionsYield
With sodium hydrogencarbonate In tetrahydrofuran; water at 0℃; Inert atmosphere; Schlenk technique;93%
Stage #1: pregabilin With sodium hydroxide In 1,4-dioxane; water at 20℃; for 0.0833333h;
Stage #2: di-tert-butyl dicarbonate In 1,4-dioxane; water at 20℃; for 1.5h;
86%
With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃;63%
L-proline hydrochloride
7776-34-3

L-proline hydrochloride

pregabilin
148553-50-8

pregabilin

(S)-3-(aminomethyl)-5-methylhexanoic acid L-proline hydrochloride
1414928-44-1

(S)-3-(aminomethyl)-5-methylhexanoic acid L-proline hydrochloride

Conditions
ConditionsYield
In acetonitrile at 20℃;93%
pregabilin
148553-50-8

pregabilin

4-(2-methylpropyl)pyrrolidin-2-one
61312-87-6

4-(2-methylpropyl)pyrrolidin-2-one

Conditions
ConditionsYield
at 190℃; for 0.166667h;91%
(E)-3-phenylpropenal
14371-10-9

(E)-3-phenylpropenal

pregabilin
148553-50-8

pregabilin

5-methyl-3-({(Z)-[(2E)-3-phenylprop-2-en-1-ylidene]amino}methyl)hexanoic acid

5-methyl-3-({(Z)-[(2E)-3-phenylprop-2-en-1-ylidene]amino}methyl)hexanoic acid

Conditions
ConditionsYield
With acetic acid In ethanol at 40℃; for 6h;90%
L-Tartaric acid
87-69-4

L-Tartaric acid

pregabilin
148553-50-8

pregabilin

(S)-3-(aminomethyl)-5-methylhexanoic acid L-(+)-tartrate
1190093-69-6

(S)-3-(aminomethyl)-5-methylhexanoic acid L-(+)-tartrate

Conditions
ConditionsYield
In water; isopropyl alcohol at 0 - 20℃; Product distribution / selectivity;89%

148553-50-8Relevant articles and documents

Direct separation of pregabalin enantiomers using a zwitterionic chiral selector by high performance liquid chromatography coupled to mass spectrometry and ultraviolet detection

Chennuru, Lakshmi Narayana,Choppari, Thirupathi,Nandula, Ramakrishna Prasad,Zhang, Tong,Franco, Pilar

, (2016)

The chromatographic resolution of pregabalin enantiomers has been often achieved by derivatization of the molecule, in order to reach enough sensitivity at low concentrations of the minor enantiomer present in the active principle. In the present article, the development and optimization of two liquid chromatographic methods are presented for the direct resolution of pregabalin enantiomers on a chiral stationary phase (CSP) containing a zwitterionic selector derived from cinchona alkaloid and sulfonic acid (CHIRALPAK ZWIX). The key parameters for the separation as well as the compatibility of chromatographic conditions with different detection modes (ultraviolet and mass spectrometry) were investigated. The resulting methods were found to be selective, of high performance and low limits of detection (2 μg/mL by UV and 1 ng/mL by MS, respectively) and quantification (6 μg/mL by UV and 5 ng/mL by MS, respectively) for the minor enantiomer which is considered as a chiral impurity.

Efficient Chemoenzymatic Synthesis of Optically Active Pregabalin from Racemic Isobutylsuccinonitrile

Zhang, Qin,Wu, Zhe-Ming,Liu, Shuang,Tang, Xiao-Ling,Zheng, Ren-Chao,Zheng, Yu-Guo

, p. 2042 - 2049 (2019)

An efficient chemoenzymatic route has been developed for the synthesis of optically active pregabalin (PGB) from isobutylsuccinonitrile (IBSN). (S)-3-cyano-5-methylhexanoic acid ((S)-CMHA), a critical chiral intermediate of PGB, was synthesized using regio- and enantioselective hydrolysis of IBSN by immobilized Escherichia coli cells harboring nitrilase BrNIT from Brassica rapa. The catalytic performances of immobilized cells were investigated, and high enantioselectivity (E > 150) and substrate conversion (>41.1%) were obtained at a substrate loading of 100 g/L by immobilized cells after 12 batches of reaction. The unreacted (R)-IBSN was recycled by racemization with a high yield of 94.5%, and the resultant (S)-CMHA was hydrogenated directly to the desired PGB with a high purity of 99.6% and optical purity of 99.4%. The input of raw materials and E factor of this chemoenzymatic route were demonstrated to be much lower than those of the first- and second-generation routes for PGB synthesis.

A new synthetic route for the preparation of pregabalin

He, Chasheng,Zhai, Ziran,Zhou, Yang,Li, Jianqi,Wang, Guan

, p. 2034 - 2040 (2021)

We reported the synthesis of (S)-pregabalin in a five-step sequence with 20% overall yield. As a modification of the previously developed route, a Michael addition between CH3NO2 and chiral oxaoxazolidinone was employed as a key operation for introducing the methyleneamino group, which allowed avoiding the use of toxic cyanide reagent and led to enantiomerically pure product (>99% ee) after the recrystallization in appropriate solvent.

Enantiomerically pure synthesis of β-substituted γ- butyrolactones: A key intermediate to concise synthesis of pregabalin

Ok, Taedong,Jeon, Aram,Lee, Joohee,Jung, Hak Lim,Chang, Seop Hong,Lee, Hee-Seung

, p. 7390 - 7393 (2007)

(Chemical Equation Presented) Chiral β-substituted γ-butyrolactones are known to be important intermediates for many biologically active compounds such as γ-aminobutyric acid (GABA) derivatives and lignans. We have developed a general, convenient, and scalable synthetic method for enantiomerically pure β-substituted γ-butyrolactones, with either configuration, via nucleophilic cyclopropane ring opening of (1S,5R)- or (1R,5S)-bicyclic lactone followed by decarbethoxylation. The utility of our method was demonstrated by streamlined synthesis of pregabalin ((S)-3-isobutyl-γ-aminobutyric acid), an anticonvulsant drug for the treatment of peripheral neuropathic pain.

An enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid via asymmetric hydrogenation

Burk, Mark J.,De Koning, Pieter D.,Grote, Todd M.,Hoekstra, Marvin S.,Hoge, Garrett,Jennings, Rex A.,Kissel, William S.,Le, Tung V.,Lennon, Ian C.,Mulhern, Thomas A.,Ramsden, James A.,Wade, Robert A.

, p. 5731 - 5734 (2003)

A concise enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (1, Pregabalin) has been developed. The key step is the asymmetric hydrogenation of a 3-cyano-5-methylhex-3-enoic acid salt 2 with a rhodium Me-DuPHOS catalyst, providing the desired (S)-3-cyano-5-methylhexanoate 3 in very high ee. Subsequent hydrogenation of the nitrile 3 with a heterogeneous nickel catalyst provides Pregabalin I in excellent overall yield and purity.

METHODS FOR TREATING CHRONIC FATIGUE SYNDROME AND MYALGIC ENCEPHALOMYELITIS

-

, (2021/03/13)

In one aspect the invention relates to a method of treatment selected from the group consisting of: (a) treating a symptom such as pain in a subject identified or diagnosed as having Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); (b) treating a symptom such as pain in a subject having dysfunctional TRPM3 ion channel activity; (c) restoring NK cell function in a subject having dysfunctional TRPM3 ion channel activity; and (d) restoring calcium homeostasis in a subject having dysfunctional TRPM3 ion channel activity. The method comprises the step of administering to the subject a therapeutically effective amount of at least one therapeutic compound selected from the group consisting of: (i) an opioid receptor antagonist; (ii) an opioid antagonist; and (iii) a therapeutic compound that restores TRPM3 ion channel activity. In some embodiments the therapeutic compound is naltrexone hydrochloride.

AN IMPROVED PROCESS FOR THE PREPARATION OF PREGABALIN

-

, (2021/06/04)

The present invention relates to an improved process for the preparation of Pregabalin (I), which is simple, economical, efficient, and environment friendly, commercially viable with chemical and chiral purity at least 99.95%.

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