148553-50-8

Basic information

• Product Name: Pregabalin
• Synonyms: 3(S)-(AMINOMETHYL)-5-METHYLHEXANOIC ACID;(3S)-3-(AMINOMETHYL)-5-METHYLHEXANOIC ACID;PREGABALIN;Pregablin;3-(Aminomethyl)-5-methyl-hexanoic acid;PREDNISOLONESODIUMPHOSPHATE;(R)-Pregabalin;(S)-Pregabalin
• CAS NO: 148553-50-8
• Molecular Formula: C8H17NO2
• Molecular Weight: 159.23
• EINECS: 200-659-6
• Product Categories: APIs;Miscellaneous Biochemicals;Intermediates & Fine Chemicals;Neurochemicals;Pharmaceuticals;API;Pfizer compounds;LYRICA;Pregabaline ada@tuskwei.com whatsapp;8618031153937
• Mol File: 148553-50-8.mol

Chemical Properties

• Melting Point: 194-196°C
• Boiling Point: 274 °C at 760 mmHg
• Flash Point: 9℃
• Appearance: off-white solid
• Density: 0.997 g/cm³
• Refractive Index: 1.464
• Storage Temp.: Store at RT
• Solubility: deionized water: ≥10mg/mL
• CAS DataBase Reference: Pregabalin(CAS DataBase Reference)
• NIST Chemistry Reference: Pregabalin(148553-50-8)
• EPA Substance Registry System: Pregabalin(148553-50-8)

Safety Data

• Hazard Codes: Xn,T,F
• Statements: 63-48/22-39/23/24/25-23/24/25-11
• Safety Statements: 22-36/37-45-16-7
• RIDADR: UN1230 - class 3 - PG 2 - Methanol, solution
• Hazardous Substances Data: 148553-50-8(Hazardous Substances Data)

Usage

Description

As a follow-up to its g-aminobutyric acid (GABA) agonist gabapentin, Pfizer has developed and launched pregabalin for the treatment of epilepsy and neuropathic pain. Although pregabalin is a structural analog of GABA, it does not interact with GABA-A or GABA-B receptors or influence GABA uptake. The exact mechanism of action is unclear, but pregabalin may reduce excitatory neurotransmitter release by binding to the α2-δ protein subunit of voltage-gated calcium channels. The resulting inhibition of excess neuronal activity is believed to be the basis for pregabalin’s efficacy in epilepsy and neuropathic pain alleviation. Since the activity is attributed to the (S′)-enantiomer alone, an efficient asymmetric synthesis is employed for commercial production. The key step is the asymmetric hydrogenation of 3-cyano-5-methyl-3-hexenoic acid using a chiral rhodium catalyst to afford an intermediate that is enriched in the (S′)-enantiomer. The cyano group is ultimately reduced by routine hydrogenation with a nickel catalyst. Further enrichment of the final product is realized by selective recrystallization with (S′)-mandelic acid or simply recrystallizing from water/isopropanol. Compared to gabapentin, pregabalin is 2- to 10-fold more potent in various animal models. For example, in preventing maximal electroshock seizures (MES) in mice, pregabalin has an ED50 of 20 mg/kg p.o. versus 87 mg/kg for gabapentin. A comparable increase in potency is also observed in the rat MES model (ED50=1.8mg=kg p.o. for pregabalin versus 10.3 mg/kg for gabapentin). In addition, pregabalin’s linear pharmacokinetics (Cmax relates to dose) translates to better predictability of pharmacological effects. It has 90% oral bioavailability, with an elimination half-life of approximately 6 h. The primary route of excretion is via the renal system with negligible metabolism. Furthermore, its lack of activity at the cytochrome P450 enzymes was reflected in an absence of pharmacokinetic drug-drug interactions in relevant studies. In a placebocontrolled, fixed dose (up to 600mg/day) trial with pregabalin as an adjunctive therapy for epilepsy, 14 to 51% of patients showed at least a 50% decrease in seizure frequency with a clear dose-response relationship. In a flexible dosing group, (150 mg/day to 600 mg/day), the seizure reduction rate was 35.4%compared to 40.3% for a fixed dose of 600mg/day and 10.6% for placebo. The most common side effects were dizziness (29%) and somnolence (21%). In addition, weight gain (equal to or more than 7% increase from baseline) occurred in 40% of patients in the 12-week study; however, there was no affect on male fertility or efficacy of oral contraceptives in women. Regarding the use of pregabalin in treating painful diabetic peripheral neuropathy, oral administration of 300 and 600 mg/day t.i.d. was superior to placebo (39–48% compared to 15–18% with placebo) in relieving pain and improving pain-related sleep interference. While pregabalin was originally developed as an anticonvulsant for epilepsy, its success in treating neuropathic pain has led to its exploration in treating other CNS disorders, such as, anxiety, social phobia, and fibromyalgia.

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.

Uses

S-Enantiomer of Pregabalin. A GABA analogue used as an anticonvulsant. Anxiolytic analgesic used to treat peripheral neuropathic pain and fibromyalgia.

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.

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.

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.

Adverse effects

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

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 chemicalbook of Tian Ye.

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.

Description

Pregabalin is a second- generation antiepileptic drug (AED) known with the proprietary brand name of Lyrica? (Pfizer, Tadworth) in the UK and USA (Pfizer, New York, NY).

Chemical Properties

Off-White Solid

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.

Brand name

Lyrica (CP).

Originator

Warner-Lambert (US)

Cautions

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

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.

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).

Chemical 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.

Uses

Pregabalin is an anticonvulsant drug used for neuropathic pain, as an adjunct therapy for partial seizures, and in generalized anxiety disorder. It was designed as a more potent successor to gabapentin. Pregabalin is marketed by Pfizer under the trade nam

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

Synthetic route

(R)-3-((tert-butoxycarbonylamino)methyl)-5-methylhex-4-enoic acid (1021167-91-8) → pregabilin (148553-50-8)

Conditions	Yield
With hydrogenchloride; hydrogen; palladium dihydroxide In methanol at 20℃; under 4560.31 Torr;	100%

(S)-3-azidomethyl-5-methylhexanoic acid (157422-27-0) → pregabilin (148553-50-8)

Conditions	Yield
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 ether	59%
palladium on activated charcoal In tert-butyl methyl ether	59%

(S)-3-azidomethyl-5-methyl-hexanoic acid ethyl ester (951792-40-8) → pregabilin (148553-50-8)

Conditions	Yield
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) → pregabilin (148553-50-8)

Conditions	Yield
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) → pregabilin (148553-50-8)

Conditions	Yield
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) → pregabilin (148553-50-8)

Conditions	Yield
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) → pregabilin (148553-50-8)

Conditions	Yield
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 methanol	35%
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) → pregabilin (148553-50-8)

Conditions	Yield
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 → pregabilin (148553-50-8)

Conditions	Yield
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 → pregabilin (148553-50-8)

Conditions	Yield
With hydrogen In methanol at 20℃; under 760.051 Torr; for 6h; Reagent/catalyst;	95%

(S)-4-isobutyl-pyrrolidin-2-one (181289-23-6) → pregabilin (148553-50-8)

Conditions	Yield
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) → pregabilin (148553-50-8)

Conditions	Yield
With ammonia In methanol; water at 0℃;	93%

{(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)methyl]pentyl}carbamic acid methyl ester (930280-44-7) → pregabilin (148553-50-8)

Conditions	Yield
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) → pregabilin (148553-50-8)

Conditions	Yield
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) → pregabilin (148553-50-8)

Conditions	Yield
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 → pregabilin (148553-50-8)

Conditions	Yield
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 → pregabilin (148553-50-8)

Conditions	Yield
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) → pregabilin (148553-50-8)

Conditions	Yield
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) → pregabilin (148553-50-8)

Conditions	Yield
In tetrahydrofuran; water at 0 - 55℃; for 5h;	83%

(S)-3-[(dibenzylamino)methyl]-5-methylhexanoic acid → pregabilin (148553-50-8)

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

C13H25NO4 → pregabilin (148553-50-8)

Conditions	Yield
With water; sodium hydroxide at 24℃; Reflux;	81%

(S)-4-isobutyl-2-oxo-pyrrolidine-3-carboxylic acid → pregabilin (148553-50-8)

Conditions	Yield
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 → pregabilin (148553-50-8)

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

C21H26N2O3 → pregabilin (148553-50-8)

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

C16H29NO6 → pregabilin (148553-50-8)

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

C17H25NO4 → pregabilin (148553-50-8)

Conditions	Yield
With water; potassium hydroxide In water for 20h; Reflux;	78%

methyl (S)-3-cyano-5-methyl-hexanoate → pregabilin (148553-50-8)

Conditions	Yield
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) → pregabilin (148553-50-8)

Conditions	Yield
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) → pregabilin (148553-50-8)

Conditions	Yield
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) + pregabilin (148553-50-8) → 3-{[(α-(R)-isobutanoyloxyethoxy)carbonyl]aminomethyl}-5-(S)-methylhexanoic acid (1174748-30-1)

Conditions	Yield
In water; acetonitrile at 20℃; for 16h;	100%

(S)-1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanate (1174524-50-5) + pregabilin (148553-50-8) → 3-{[(α-(S)-isobutanoyloxyisobutoxy)carbonyl]aminomethyl}-5-(S)-methylhexanoic acid (1179336-90-3)

Conditions	Yield
In water; acetonitrile at 20℃; for 6h;	100%

{[(1R)-Benzoyloxyethoxy]carbonyloxy}succinimide (1174524-53-8) + pregabilin (148553-50-8) → (3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoic acid (1174748-47-0)

Conditions	Yield
In water; acetonitrile at 20℃; for 16h;	100%

lauric acid (143-07-7) + pregabilin (148553-50-8) → (S)-3-(aminomethyl)-5-methylhexanoic acid laurate (1414928-47-4)

Conditions	Yield
In isopropyl alcohol for 1.5h; Product distribution / selectivity;	100%

maleic acid (110-16-7) + pregabilin (148553-50-8) → (S)-3-(aminomethyl)-5-methylhexanoic acid maleate (1414928-41-8)

Conditions	Yield
In 2-methylpropyl acetate for 0.75h; Product distribution / selectivity;	100%

benzoic acid (65-85-0) + pregabilin (148553-50-8) → (S)-3-(aminomethyl)-5-methylhexanoic acid benzoate (1414928-43-0)

Conditions	Yield
for 0.75h; Product distribution / selectivity;	100%

Octanoic acid (124-07-2) + pregabilin (148553-50-8) → (S)-3-(aminomethyl)-5-methylhexanoic acid caprylate (1414928-45-2)

Conditions	Yield
In tert-butyl methyl ether for 0.75h;	100%

1-decanoic acid (334-48-5) + pregabilin (148553-50-8) → (S)-3-(aminomethyl)-5-methylhexanoic acid caprate (1414928-46-3)

Conditions	Yield
In tert-butyl methyl ether for 0.75h;	100%

di-tert-butyl dicarbonate (24424-99-5) + pregabilin (148553-50-8) → 3-((tert-butoxycarbonylamino)methyl)-5-methylhexanoic acid (228104-41-4)

Conditions	Yield
With sodium hydroxide In 1,4-dioxane; water	98%

pregabilin (148553-50-8) → (S)-4-isobutyl-pyrrolidin-2-one (181289-23-6)

Conditions	Yield
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 + pregabilin (148553-50-8) → (S)-Mandelic acid (17199-29-0)

Conditions	Yield
With pyrographite In isopropyl alcohol at 0 - 85℃; for 4h;	95%

di-tert-butyl dicarbonate (24424-99-5) + pregabilin (148553-50-8) → (S)-3-(((tert-butoxycarbonyl)amino)methyl)-5-methylhexanoic acid (649748-09-4)

Conditions	Yield
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) + pregabilin (148553-50-8) → (S)-3-(aminomethyl)-5-methylhexanoic acid L-proline hydrochloride (1414928-44-1)

Conditions	Yield
In acetonitrile at 20℃;	93%

pregabilin (148553-50-8) → 4-(2-methylpropyl)pyrrolidin-2-one (61312-87-6)

Conditions	Yield
at 190℃; for 0.166667h;	91%

(E)-3-phenylpropenal (14371-10-9) + pregabilin (148553-50-8) → 5-methyl-3-({(Z)-[(2E)-3-phenylprop-2-en-1-ylidene]amino}methyl)hexanoic acid

Conditions	Yield
With acetic acid In ethanol at 40℃; for 6h;	90%

L-Tartaric acid (87-69-4) + pregabilin (148553-50-8) → (S)-3-(aminomethyl)-5-methylhexanoic acid L-(+)-tartrate (1190093-69-6)

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

Upstream product

• 14855-33-5 6,13-diazadispiro[4.2.4.2]tetradecane-7,14-dione 
• 14855-31-3 1,3-O-Dibenzyl-N-acetyl-β-D-glucosaMine 
• 148550-96-3 N~2~,N~2~-dimethyl-N-(5-methyl-4-oxo-2-{[(1R)-1-phenylethyl]amino}-4H-3,1-benzoxazin-6-yl)glycinamide 
• 1485506-79-3 N-(2,3-dihydroxypropyl)-4-hydroxybenzamide 
• 148550-52-1 Carbamic acid, (2-ethynylphenyl)-, ethyl ester (9CI) 
• 148550-51-0 ETHYL 2-(METHYLSULFONYL)PYRIMIDINE-5-CARBOXYLATE 
• 148-54-9 5-amino-2-[(2-methoxyphenyl)amino]benzenesulphonic acid 
• 148547-19-7 Methyl 4-bromo-3-methylbenzoate 
• 148546-99-0 3-(4-Methylpiperazin-1-yl)aniline 
• 148546-97-8 1-METHYL-4-(3-NITROPHENYL)PIPERAZINE 
• 148546-91-2 tert-butyl 4-(5-aMino-2-Methoxyphenyl)piperazine-1-carboxylate 
• 148546-90-1 1-(5-AMINO-2-METHOXYPHENYL)PIPERAZINE 
• 148546-82-1 4-Methylpyridine-3-boronic acid 
• 148546-78-5 1-(5-AMINO-2-METHOXYPHENYL)-4-METHYLPIPERAZINE 

Downstream Products

• 148553-51-9 Hexanoic acid,3-(aminomethyl)-5-methyl-, (3R)- 
• 1485536-93-3 2-(DibroMoMethyl)-4-fluorobenzonitrile 
• 14855-40-4 Z-PRO-PHE-HIS-LEU-LEU-VAL-TYR-SER-BETANA 
• 148554-65-8 SECO RAPAMYCIN SODIUM SALT 
• 148555-10-6 (3R,3aS,6aS)-3-hydroxy-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2-one 
• 148556-27-8 BPV(PIC) 
• 148556-68-7 1,4-Benzenedicarboxylic acid polymer with 1,2-ethanediol, 2,2-[(1-methyl ethylidene)bis(4,1-phenyleneoxy)] bis[ethanol] and 1,1-[(1-methylethylidene) bis(4,1-phenyleneoxy)] bis[2-propanol] 
• 148556-87-0 N-Methyl-8-nitro-7-isoquinolinamine 
• 14855-76-6 METHYL GREEN 
• 14855-77-7 3,5-Bis(acetylamino)-2,4,6-tri(131I)iodobenzoic acid sodium salt 
• 1485583-09-2 1-(2,4-dichlorophenyl)-3-(2,3-dimethoxyphenyl)-2-propen-1-one 
• 148559-83-5 Galliumdiethylbromid 
• 148560-86-5 3,5-DIFLUORO-4'-METHOXYBENZOPHENONE 
• 148-56-1 flumethiazide