104632-25-9

Basic information

• Product Name: Pramipexole dihydrochloride
• Synonyms: PRAMIPEXOLE DIHYDROCHLORIDE;PRAMIPEXOLE HCL;PRAMIPEXOLE HYDROCHLORIDE;PRAMIPEXOL HCL;(s)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride;PramipexoleDihcl;(S)-2-Amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazol2HCltetrahydrobenzothiazol;(s)-4,5,6,7-Tetrahydro-N6-propyl-2,6-benzothiazolediamine, Dihydrochloride
• CAS NO: 104632-25-9
• Molecular Formula: C₁₀H₁₇N₃S*2ClH
• Molecular Weight: 284.25
• EINECS: 1806241-263-5
• Product Categories: Antiparkinsonian;All Inhibitors;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;APIs;Chiral Reagents;Sulfur & Selenium Compounds;API
• Mol File: 104632-25-9.mol
• Article Data: 24

Chemical Properties

• Melting Point: 288-290°C
• Boiling Point: 378 °C at 760 mmHg
• Flash Point: 182.4 °C
• Appearance: white to off-white/
• Vapor Pressure: 6.49E-06mmHg at 25°C
• Storage Temp.: Desiccate at RT
• Solubility: H2O: >20mg/mL
• CAS DataBase Reference: Pramipexole dihydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Pramipexole dihydrochloride(104632-25-9)
• EPA Substance Registry System: Pramipexole dihydrochloride(104632-25-9)

Safety Data

• WGK Germany: 3
• Hazardous Substances Data: 104632-25-9(Hazardous Substances Data)

Usage

Drug for treatment of Parkinson syndrome

Pramipexole hydrochloride is a kind of drugs for treatment of Parkinson syndrome. It belongs to selective non-ergot dopamine receptor agonist. It was first successfully developed by Boehringer Ingelheim Company (Germany). It is a prescription drugs of dopamine receptor agonist applied in the largest amount of the world. In May, 1997, it had been approved for the first time by FDA for the treatment of idiopathic Parkinson's disease. It can reduce the symptoms and sign, and can either be used alone or in combination with levodopa. The trade name of the good marketed in the United States is Mirapex, which is the first drugs approved the FDA during the past six years for treatment of Parkinson syndrome. In 2007, it has entered into market in China with the commodity name being sifrol for the treatment of the signs and symptoms of idiopathic Parkinson's disease, being used either alone (without levodopa) or in combination with levodopa. The two major efficacy characteristics of pramipexole hydrochloride in treatment of Parkinson's disease: 1. It can relieve the motor symptoms of Parkinson's disease: Parkinson's disease is cause due to the dopamine deficiency resulting from the loss of dopaminergic neuron, leading to patients get a series of symptoms such as tremors, muscle rigidity, slow movement and so on. Pramipexole hydrochloride can highly selective act on dopaminergic D2 and D3 receptors, thereby, stimulating the release of dopamine in the brain and alleviating the motor symptoms. Shannon et al have shown that early Parkinson's disease patients who has received pramipexole monotherapy can effectively have their motor symptoms be within control and can maintain daily living. When being used in combination with levodopa, pramipexole can effectively improve both the ADL score and the motor symptoms score of patients with advanced Parkinson's disease, and thus making the life of the patients with advanced Parkinson's disease more active. 2. it can significantly alleviate the depressive symptoms associated with Parkinson's disease: the pramipexole hydrochloride is a kind of agonists of dopamine D2, D3 receptor. The dopamine D3 receptor system may be associated with the patient's mood and behavior. Since pramipexole can selectively stimulate the D3 receptor with a higher agonist efficacy than D2 receptors, it can significantly relieve symptoms of depression. In study of Barone (Italy) et al, when patients with Parkinson’s disease had been treated with pramipexole or sertraline, the proportion of patients with alleviated depression symptoms in pramipexole group was significantly higher than that of the sertraline group. Researchers believe that dopamine agonists (pramipexole) can substitute antidepressants to treat the depression of patients with Parkinson disease. Pramipexole has protective effect on damaged neurons as well as excellent control of the jitter symptom. It has the least side effects in the field of Parkinson syndrome. Moreover, it has a large scope for adjusting drug in later phase, which is good for the following treatment. It can prevent the nerve damage caused by long-term use of levodopa, delaying the time needed for levodopa treatment as well as reducing the dose of levodopa. The above information is edited by the lookchem of Dai Xiongfeng.

Toxicology

Genetic Toxicity: The testing result of pramipexole in Ames test, HGRRT V79 gene mutation assay, CHO cell chromosome aberration test, mouse micronucleus test were all negative. Reproductive toxicity: within the fertility experiment, administration of rats with 2.5 mg/kg/day of pramipexole (according to the estimation based on mg/m2, this is equivalent to 5.4 fold of the maximum recommended human dose (1.5mg, tid)) causes estrous cycle extension as well as the reduction of the implantation rate. This may be related to the reduce serum prolactin levels caused by pramipexole (during the early phase of rat pregnancy, the embryo implantation and maintenance need prolactin while this is not required for human and rabbit). During the teratogenic sensitive period of pregnant rats,, administration of pramipexole in 1.5mg/kg day (based on the estimation of plasma AUC, this is equivalent to 4.3 fold of the AUC of maximum recommended human dose) can increase the incidence of total absorption fetal which may be related to that pramipexole can cause the reduced serum prolactin levels. During the teratogenic sensitive period of pregnant rabbits, administration of pramipexole in 10mg/kg/day (the plasma AUC is 71 times as high as the AUC of the maximum recommended dose of AUC) causes no abnormal behavior. During the perinatal period of pregnant rat, administration of pramipexole in 0.5mg/kg/day (based on the calculation of mg/m2, this is equivalent to the maximum recommended clinical dose for human) or higher doses has no adverse effect on the growth of rat offspring after birth. Carcinogenicity: applying drug-admixed food method to mouse and rat for administration of pramipexole in 0.3, 2, 10mg/kg/day (based on the calculation of mg/m2, this is equivalent to 0.3 fold, 2.2 fold and 11 fold, respectively of the maximum recommended dose of human ) or 0.3, 2,8mg/kg/day (estimated from plasma AUC, this is equivalent to 0.3 fold, 2.5 fold and 12.5 fold, respectively of AUC of the maximum recommended human dose) causes no increase in the incidence of tumor.

Clinical evaluation of the treatment of Parkinson's disease

Clinical trials including 4 placebo-control experiment has demonstrated the effectiveness of pramipexole in treating PD motor symptoms. A prospective clinical study in German had confirmed the efficacy of pramipexole in treating PD related akinesia, rigidity and tremors and other symptoms. The most rigorous and longest observation study comes from the Parkinson’s Research Group (PSG) of United States and Canada which had conducted four-year multi-center, double-blind, parallel, randomized, controlled study. This study compared the long-term efficacy of pramipexole and levodopa in treating early phase Parkinson’s disease when being used alone; the primary outcome variables: the first time when dopaminergic complications (loss efficacy, dyskinesia, and "switch" motor fluctuations) occurs, the change of the unified Parkinson's disease assessment scale (UPDRS) and scale of life quality. The analysis results after 2 years treatment had demonstrated that, the incidence of the dopaminergic complication in pramipexole group (28%) was significantly lower than that in the levodopa group (51%) (OR value 0.45, P <0.001);Compared with the baseline period, the overall UPDRS score of pramipexole group has increased by 4.5 points after two years which is significantly lower than that of the levodopa group (9.2) (P <0.001). After 4 years of analysis: the incidence of dyskinesia in the pramipexole group (24.5%) was significantly lower than that of the levodopa group (54%) (OR value 0.37, P <0.001). The incidence of decreased efficacy of pramipexole group (47%) was also significantly lower than that of the levodopa group (62.7%) (OR value 0.68, P = 0.02). However, the incidence of movement rigidity in the pramipexole group (37.1%) is greater than that of the levodopa group (25.3%) (P = 0.01); Compared with baseline, improvement in UPDRS score of pramipexole group after 4 years [(-3.2 ± 17.3) min] is lower than levodopa group [(2.0 ± 15.4) min] (0.03). In addition, no significant statistic difference has been observed for the two groups in improving the quality of life. Studies suggest that while pramipexole is slightly inferior t levodopa in alleviating the PD symptoms, but pramipexole can significantly reduce the incidence of complications of dopaminergic movement. Because younger PD patients have a high possibility of suffering from dopaminergic motor complications than elderly patients, younger PD patients should be subject to pramipexole monotherapy in early phase.

Advanced Parkinson's disease (PD)

It has been reported since 1995 that pramipexole is effective in treating patients with advanced PD. In 1997, Lieberman et al (United States) had published the results of a double-blind, placebo-controlled, multi-center study for evaluating the efficacy and safety of pramipexole in treatment of the advanced PD patients receiving levodopa but have already gotten symptom fluctuations. Study included 360 patients and results had showed that pramipexole can improve patients' motor symptoms during "on" and "off" period with reducing the "off" time as well as reducing the severity of the symptoms during the "off" period, enabling the reduction usage of levodopa. A 12-week domestic, multi-center, randomized, double-blind, bromocriptine-controlled clinical study on the efficacy of pramipexole in treating Parkinson's disease have found that, for the ratio of volunteers patients with UPDRS II-IV being larger than 30%, overall clinical evaluation as well as drug onset time, pramipexole was always better than bromocriptine (P <0.05). Europe has conducted a multicenter, double-blind, placebo-controlled study on the efficacy pramipexole in long-term treatment of patients with advanced PD. This study included a total of 354 cases of advanced PD patients who were receiving levodopa therapy but have already gotten symptom fluctuation, wherein 174 patients received the treatment of pramipexole and levodopa and 180 patients received placebo and levodopa treatment with observation period up to 57 months. The results showed that: Pramipexole can increase the II and III part of UPDRS score by 30% and reduce the “off” time in symptoms of fluctuations by 2.5 per day; Pramipexole can also significantly ease resting tremor. Moreover, 30.1% of the patients in the pramipexole group reduced the usage amount of levodopa while the ratio is only 12.8% in the placebo group. These studies suggest that pramipexole is effective in treating advanced PD as an adjunctive therapy to levodopa. The drug can not only effectively improve the motor symptoms of early and advanced Parkinson's disease, delay and reduce the occurrence and extent of levodopa-related motor complications, but also alleviate the symptoms of depression associated with Parkinson's disease. The drug has a rapid effect, long-lasting action with being safe for medication and small side effects. It is superior to bromocriptine in alleviating the symptoms of advanced PD dysfunction and has recognized and accepted by doctors and PD patients in clinical practice

Uses

Different sources of media describe the Uses of 104632-25-9 differently. You can refer to the following data:
1. It is used for treating Parkinsonism. It can also be used as pharmaceutical raw materials.
2. A dopamine-D2-receptor agonist. Antiparkinsonian
3. A dopamine-D2-receptor agonist. Antiparkinsonian.

Description

Different sources of media describe the Description of 104632-25-9 differently. You can refer to the following data:
1. (S)-Pramipexole is a dopamine D2S, D2L, D3, and D4 receptor agonist (EC50s = 426.58, 338.84, 2.24, and 128.82 nM, respectively, in a [35S]GTPγS binding assay). It is also a partial agonist of α2A-adrenergic receptors (α2A-ARs; EC50 = 3,548.13 nM). (S)-Pramipexole is selective for dopamine D2-4 receptors (Kis = 954.99, 1,698.24, 12.59, 128.82 nM for for D2S, D2L, D3, and D4 receptors, respectively, in a radioligand binding assay) over D1 and D5 receptors (Kis = >10,000 nM for both). It prevents MPTP-induced decreases in the number of dopaminergic neurons in the substantia nigra pars compacta in common marmosets when administered at a dose of 60 μg/kg per day before, during, and after administration of MPTP. Formulations containing (S)-pramipexole have been used in the treatment of Parkinson''s disease and restless legs syndrome.
2. Mirapex, an non ergot derivative, was launched in the US for treatment of Parkinson's disease. It can be prepared by two related routes, 5 steps and 3 steps, both involving an optical resolution with L-(+)-tartaric acid to afford the (S)-isomer. Mechanistically, it is a presynaptic dopamine D2 autoreceptor agonist which also activates D3-receptors. It is well absorbed from the GI and excreted in the urine essentially unchanged with a half-life of 8-12 hr. Mirapex had favorable effects on the symptoms without levodopa for patients with advanced PD and allowed a 27% reduction in use of levodopa in combination therapy. It had an adverse events profile similar to other dopamine agonists and in advanced patients reduced the mean "on-off" hr/day from 6 to 4. It was safe but not efficacious in all patients.

Chemical Properties

White Crystalline Powder

Originator

Boehringer Ingelheim (Germany)

Definition

ChEBI: A hydrochloride that is the anhydrous dihydrochloride salt of pramipexole.

Manufacturing Process

75.5 g (0.5 mol) of 4-aminocyclohexanol hydrochloride and 74.0 g (0.5 mol) of phthalic acid anhydride are mixed with 65 g (0.5 mol) of ethyldiisopropyl amine and 1000 ml of toluene and boiled for 36 hours with a water separator. Then water is added, the toluene phase is separated off and the aqueous phase is extracted several times with chloroform. The organic phases are combined, dried and concentrated. The concentrated residue is recrystallised from isopropanol and 4-(phthalimido)-cyclohexanol was obtained. Yield: 95 g (77.8%). Melting point 175°-176°C.95 g (0.388 mol) of 4-(phthalimido)-cyclohexanol are dissolved in 600 ml of chloroform and, after the addition of 450 ml of water and 120 ml of sulfuric acid, 90 g (0.3 mol) of potassium dichromate are added in batches. The internal temperature of the mixture is maintained at between 25° and 30°C by slight cooling. The mixture is stirred for a further 3 hours, then the chloroform phase is separated off and the mixture extracted twice more with chloroform. After drying and concentration of the extracts 82 g (86.9%) of 4(phthalimido)-cyclohexanone was obtained.48.6 g (0.2 mol) of 4-(phthalimido)cyclohexanone are dissolved in glacial acetic acid, mixed with 36% of hydrobromic acid in glacial acetic acid and then 32 g (0.2 mol) of bromine in glacial acetic acid is added dropwise with cooling. The mixture is then concentrated by evaporation in vacuo and the residue is triturated several times with diethylether. The ether extracts are discarded and the residue is dissolved in of ethanol. After thiourea have been added the mixture is refluxed for 5 hours. It is then concentrated by evaporation, made alkaline with sodium hydroxide solution and extracted with chloroform. After drying and concentration of the extracts, the residue is purified by column chromatography on silica gel (eluant: chloroform/methanol = 1/1). The 2-amino-6-phthalimido-4,5,6,7-tetrahydro-benzthiazol was obtained. Melting point 244-246°C, dec. Yield: 30 g (50%).9.5 g (31.7 mmol) of 2-amino-6-phthalimido-4,5,6,7-tetrahydro-benzthiazole are suspended in 100 ml of ethanol and, after the addition of 1.8 g (36 mmol) of hydrazine hydrate, refluxed for 2 hours. The mixture is then concentrated and purified by column chromatography on silica gel using methanol as eluant. The 2,6-diamino- 4,5,6,7-tetrahydro-benzthiazole was obtained.To a solution of 2,6-diamino- 4,5,6,7-tetrahydro-benzthiazole in dimethylformamide are added n-propanal and the mixture is heated to 50°C for 1 hour. After cooling, the reaction solution is mixed with sodium borohydride and heated to 50°C for 30 min. The solvent is largely eliminated in vacuo. Whilst cooling with ice, the residue is mixed with water and 2 N hydrochloric acid until a pH of 1 is obtained. The aqueous solution is exwith ethylacetate and the organic phase discarded. The aqueous phase is mixed with potassium carbonate until an alkaline reaction is obtained and then extracted with ethyl acetate. The organic phase is dried and concentrated. The 2-amino-6-n-propylamino-4,5,6,7-tetrahydro-benzthiazole dihydrochloride crystallizes out when ethereal hydrochloric acid is added. Yield: 42%. Melting point: 286°-288°C.

Brand name

Mirapex (Boehringer Ingelheim).

Therapeutic Function

Antiparkinsonian, Antipsychotic

General Description

Pramipexole dihydrochloride,(S)-2-amino-6-propylamino-dihydrochloride(Mirapex), is a white to off-white powder soluble in water,slightly soluble in methanol and ethanol, and practically insolublein dichloromethane. Following oral administration,pramipexole is readily absorbed. Pharmacokinetic propertiesdiffer between men and women, with area under the curve(AUC) for each dose level being 35% to 43% greater inwomen, mainly because of a 24% to 27% lower oral clearance.The drug undergoes minimal hepatic biotransformationand is excreted virtually unchanged in the urine by the renaltubular secretion. Pramipexole interacts with drugs excretedby renal tubular secretion (H2-antagonists, diuretics, verapamil,quinidine, quinine), which leads to a decreased clearanceof pramipexole.44,45 Pramipexole is indicated fortreatment of the signs and symptoms of idiopathic PD, aloneor in combination with levodopa. It is also indicated for symptomatictreatment of moderate to severe idiopathic restlesslegs syndrome (RLS).

Biochem/physiol Actions

Pramipexole is a dopamine agonist active at D3 and D2 receptor subtypes. Pramipexole has been found to have neuroprotective effects independent of its dopamine receptor agonism. It reduces mitochondrial reactive oxygen species (ROS) production and inhibits the activation of apoptotic pathways.

InChI:InChI=1/C10H17N3S.ClH/c1-2-5-12-7-3-4-8-9(6-7)14-10(11)13-8;/h7,12H,2-6H2,1H3,(H2,11,13);1H

Synthetic route

(S)‑2‑amino‑6‑propionamido‑4,5,6,7‑tetrahydrobenzothiazole (106006-84-2) → pramipexole dihydrochloride (104632-25-9)

Conditions	Yield
Stage #1: (S)‑2‑amino‑6‑propionamido‑4,5,6,7‑tetrahydrobenzothiazole With potassium borohydride; triethylamine; lithium chloride In tetrahydrofuran at 20℃; for 7h; Inert atmosphere; Reflux; Stage #2: With hydrogenchloride at -5 - 20℃; for 5h; Reagent/catalyst; Solvent; Temperature; Reflux;	78.2%
Stage #1: (S)‑2‑amino‑6‑propionamido‑4,5,6,7‑tetrahydrobenzothiazole With chloro-trimethyl-silane In dichloromethane at 0 - 15℃; Inert atmosphere; Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran; dichloromethane at -10 - 0℃; Inert atmosphere;	72%
Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 0 - 50 °C 1.2: 0.17 h / 10 °C 2.1: hydrogenchloride / water; methanol / 0.75 h / 25 - 30 °C View Scheme
Stage #1: (S)‑2‑amino‑6‑propionamido‑4,5,6,7‑tetrahydrobenzothiazole With sodium bis(2-methoxyethoxy)aluminium dihydride In toluene at 80℃; for 6h; Stage #2: With hydrogenchloride In water; isopropyl alcohol at 20℃; under 75.0075 Torr; for 1h; Temperature; Pressure;

2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole p-toluenesulfonic acid (943319-02-6) → pramipexole dihydrochloride (104632-25-9)

Conditions	Yield
With acetyl chloride In isopropyl alcohol at 5 - 20℃; for 12.5h;	86%
Stage #1: 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole p-toluenesulfonic acid With hydrogenchloride In water at 0℃; for 0.25h; Stage #2: With sodium hydroxide In water at 0℃; for 3h;	78%

(S)-t-butyl-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl(propyl)carbamate (1265141-51-2) → pramipexole dihydrochloride (104632-25-9)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran at 20 - 25℃; for 12h;	85%

pramipexole (104632-26-0) → pramipexole dihydrochloride (104632-25-9)

Conditions	Yield
With hydrogenchloride In water; acetone at 0 - 3℃; for 2h; pH=1.5; Product distribution / selectivity;	98%
With hydrogenchloride In water; isopropyl alcohol at 20℃; for 2h;	95.8%
With hydrogenchloride In water; acetone at 20℃; for 3h; Large scale;	90.9%

pramipexole (HCl) (943319-04-8) → pramipexole dihydrochloride (104632-25-9)

Conditions	Yield
With hydrogenchloride; water In methanol at 3 - 8℃; for 2h;	36%

(6S,7S)-2-amino-7-hydroxy-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole (1001648-71-0) → pramipexole dihydrochloride (104632-25-9)

Conditions	Yield
Stage #1: (6S,7S)-2-amino-7-hydroxy-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole With hydrogenchloride; formic acid In water Stage #2: With hydrogen; palladium on activated carbon In water Product distribution / selectivity;	87%

propionaldehyde (123-38-6) + (S)-4,5,6,7-tetrahydrobenzo[d]thiazol-2,6-diamine (106092-09-5) → pramipexole dihydrochloride (104632-25-9)

Conditions	Yield
Stage #1: propionaldehyde; (S)-4,5,6,7-tetrahydrobenzo[d]thiazol-2,6-diamine With sulfuric acid In methanol at 0℃; Stage #2: With sodium tetrahydroborate In methanol at 0 - 20℃; Stage #3: With hydrogenchloride In ethanol at 0℃; for 8h;

(S)-4,5,6,7-tetrahydrobenzo[d]thiazol-2,6-diamine (106092-09-5) → pramipexole dihydrochloride (104632-25-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / methanol / 1.5 h / 10 - 20 °C 2.1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 0 - 50 °C 2.2: 0.17 h / 10 °C 3.1: hydrogenchloride / water; methanol / 0.75 h / 25 - 30 °C View Scheme
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 2.1: hydrogenchloride / water / 0.25 h / 0 °C 2.2: 3 h / 0 °C View Scheme
Multi-step reaction with 3 steps 1: sulfuric acid; sodium tetrahydroborate / dichloromethane; methanol / 3 - 8 °C 2: hydrogenchloride / water 3: hydrogenchloride; water / methanol / 2 h / 3 - 8 °C View Scheme

N-(4-oxocyclohexyl)acetamide (27514-08-5) → pramipexole dihydrochloride (104632-25-9)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: bromine; acetic acid / 0.75 h / 25 - 35 °C 1.2: 3 h / Reflux 2.1: water; sulfuric acid / 10 h / Reflux 2.2: 1.5 h / 0 - 30 °C 3.1: water / 70 °C / Reflux; Resolution of racemate 4.1: hydrogenchloride / water / carbon treatment 4.2: 1.5 h / 25 - 30 °C 5.1: triethylamine / methanol / 1.5 h / 10 - 20 °C 6.1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 0 - 50 °C 6.2: 0.17 h / 10 °C 7.1: hydrogenchloride / water; methanol / 0.75 h / 25 - 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: bromine / water / 2 h / 45 - 80 °C / Large scale 1.2: 3 h / Reflux; Large scale 2.1: ethanol / 5 h / 50 °C 3.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 6 h / 80 °C 3.2: 1 h / 20 °C / 75.01 Torr View Scheme

2,6-diamino-4,5,6,7-tetrahydro-benzthiazole (106006-83-1) → pramipexole dihydrochloride (104632-25-9)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: water / 70 °C / Reflux; Resolution of racemate 2.1: hydrogenchloride / water / carbon treatment 2.2: 1.5 h / 25 - 30 °C 3.1: triethylamine / methanol / 1.5 h / 10 - 20 °C 4.1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 0 - 50 °C 4.2: 0.17 h / 10 °C 5.1: hydrogenchloride / water; methanol / 0.75 h / 25 - 30 °C View Scheme

N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)acetamide hydrobromide (104617-50-7) → pramipexole dihydrochloride (104632-25-9)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: water; sulfuric acid / 10 h / Reflux 1.2: 1.5 h / 0 - 30 °C 2.1: water / 70 °C / Reflux; Resolution of racemate 3.1: hydrogenchloride / water / carbon treatment 3.2: 1.5 h / 25 - 30 °C 4.1: triethylamine / methanol / 1.5 h / 10 - 20 °C 5.1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 0 - 50 °C 5.2: 0.17 h / 10 °C 6.1: hydrogenchloride / water; methanol / 0.75 h / 25 - 30 °C View Scheme

(S)-4,5,6,7-tetrahydro-benzothiazole-2,6-diamine tartrate trihydrate (873431-80-2) → pramipexole dihydrochloride (104632-25-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water / carbon treatment 1.2: 1.5 h / 25 - 30 °C 2.1: triethylamine / methanol / 1.5 h / 10 - 20 °C 3.1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 4 h / 0 - 50 °C 3.2: 0.17 h / 10 °C 4.1: hydrogenchloride / water; methanol / 0.75 h / 25 - 30 °C View Scheme

2-amino-6-oxo-4,5,6,7-tetrahydrobenzothiazole (113030-24-3) → pramipexole dihydrochloride (104632-25-9)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: 0.5 h / 100 °C 2.1: Sucrose / aq. phosphate buffer; n-heptane / 16 h / 30 °C / pH 7 3.1: pyridine / 2 h / 0 - 20 °C 4.1: sodium azide / N,N-dimethyl-formamide / 6 h / 20 - 70 °C / Inert atmosphere 5.1: polymer bonded triphenyl phosphine / tetrahydrofuran; water / 12 h / 40 °C 6.1: hydrogenchloride; water / tetrahydrofuran / 12 h / 80 °C 7.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 8.1: hydrogenchloride / water / 0.25 h / 0 °C 8.2: 3 h / 0 °C View Scheme

(R)-2-acetylamino-6-hydroxy-4,5,6,7-tetrahydrobenzothiazole → pramipexole dihydrochloride (104632-25-9)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: pyridine / 2 h / 0 - 20 °C 2.1: sodium azide / N,N-dimethyl-formamide / 6 h / 20 - 70 °C / Inert atmosphere 3.1: polymer bonded triphenyl phosphine / tetrahydrofuran; water / 12 h / 40 °C 4.1: hydrogenchloride; water / tetrahydrofuran / 12 h / 80 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 6.1: hydrogenchloride / water / 0.25 h / 0 °C 6.2: 3 h / 0 °C View Scheme

(R)-2-acetylamino-6-hydroxy-4,5,6,7-tetrahydrobenzothiazole, 6-tosylate → pramipexole dihydrochloride (104632-25-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium azide / N,N-dimethyl-formamide / 6 h / 20 - 70 °C / Inert atmosphere 2.1: polymer bonded triphenyl phosphine / tetrahydrofuran; water / 12 h / 40 °C 3.1: hydrogenchloride; water / tetrahydrofuran / 12 h / 80 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 5.1: hydrogenchloride / water / 0.25 h / 0 °C 5.2: 3 h / 0 °C View Scheme

(S)-2-acetylamino-6-azido-4,5,6,7-tetrahydrobenzothiazole → pramipexole dihydrochloride (104632-25-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: polymer bonded triphenyl phosphine / tetrahydrofuran; water / 12 h / 40 °C 2.1: hydrogenchloride; water / tetrahydrofuran / 12 h / 80 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 4.1: hydrogenchloride / water / 0.25 h / 0 °C 4.2: 3 h / 0 °C View Scheme

(S)-2-acetylamino-6-amino-4,5,6,7-tetrahydrobenzothiazole → pramipexole dihydrochloride (104632-25-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride; water / tetrahydrofuran / 12 h / 80 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 3.1: hydrogenchloride / water / 0.25 h / 0 °C 3.2: 3 h / 0 °C View Scheme

cyclohexanedione monoethylene ketal (4746-97-8) → pramipexole dihydrochloride (104632-25-9)

Conditions

Yield

Multi-step reaction with 11 steps 1.1: triethylamine / dichloromethane / 1 h / 0 °C / Inert atmosphere 2.1: sodium acetate; N-Bromosuccinimide / tetrahydrofuran; water / 2 h / 20 °C 2.2: 20 - 80 °C 3.1: hydrogenchloride; water / tetrahydrofuran / 4 h / Reflux 4.1: 0.5 h / 100 °C 5.1: Sucrose / aq. phosphate buffer; n-heptane / 16 h / 30 °C / pH 7 6.1: pyridine / 2 h / 0 - 20 °C 7.1: sodium azide / N,N-dimethyl-formamide / 6 h / 20 - 70 °C / Inert atmosphere 8.1: polymer bonded triphenyl phosphine / tetrahydrofuran; water / 12 h / 40 °C 9.1: hydrogenchloride; water / tetrahydrofuran / 12 h / 80 °C 10.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 11.1: hydrogenchloride / water / 0.25 h / 0 °C 11.2: 3 h / 0 °C View Scheme

1,4-cyclohexanedione-1-ethylene acetal 4-trimethylsilyl enol ether (144810-01-5) → pramipexole dihydrochloride (104632-25-9)

Conditions

Yield

Multi-step reaction with 10 steps 1.1: sodium acetate; N-Bromosuccinimide / tetrahydrofuran; water / 2 h / 20 °C 1.2: 20 - 80 °C 2.1: hydrogenchloride; water / tetrahydrofuran / 4 h / Reflux 3.1: 0.5 h / 100 °C 4.1: Sucrose / aq. phosphate buffer; n-heptane / 16 h / 30 °C / pH 7 5.1: pyridine / 2 h / 0 - 20 °C 6.1: sodium azide / N,N-dimethyl-formamide / 6 h / 20 - 70 °C / Inert atmosphere 7.1: polymer bonded triphenyl phosphine / tetrahydrofuran; water / 12 h / 40 °C 8.1: hydrogenchloride; water / tetrahydrofuran / 12 h / 80 °C 9.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 10.1: hydrogenchloride / water / 0.25 h / 0 °C 10.2: 3 h / 0 °C View Scheme

2-amino-6-(ethylenedioxy)-4,5,6,7-tetrahydrobenzothiazole (159015-33-5) → pramipexole dihydrochloride (104632-25-9)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: hydrogenchloride; water / tetrahydrofuran / 4 h / Reflux 2.1: 0.5 h / 100 °C 3.1: Sucrose / aq. phosphate buffer; n-heptane / 16 h / 30 °C / pH 7 4.1: pyridine / 2 h / 0 - 20 °C 5.1: sodium azide / N,N-dimethyl-formamide / 6 h / 20 - 70 °C / Inert atmosphere 6.1: polymer bonded triphenyl phosphine / tetrahydrofuran; water / 12 h / 40 °C 7.1: hydrogenchloride; water / tetrahydrofuran / 12 h / 80 °C 8.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 9.1: hydrogenchloride / water / 0.25 h / 0 °C 9.2: 3 h / 0 °C View Scheme

2-Acetylamino-6-oxo-4,5,6,7-tetrahydrobenzothiazole (404892-23-5) → pramipexole dihydrochloride (104632-25-9)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: Sucrose / aq. phosphate buffer; n-heptane / 16 h / 30 °C / pH 7 2.1: pyridine / 2 h / 0 - 20 °C 3.1: sodium azide / N,N-dimethyl-formamide / 6 h / 20 - 70 °C / Inert atmosphere 4.1: polymer bonded triphenyl phosphine / tetrahydrofuran; water / 12 h / 40 °C 5.1: hydrogenchloride; water / tetrahydrofuran / 12 h / 80 °C 6.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 7.1: hydrogenchloride / water / 0.25 h / 0 °C 7.2: 3 h / 0 °C View Scheme

pramipexole dihydrochloride (104632-25-9) → pramipexole (104632-26-0)

Conditions	Yield
With potassium hydroxide In water at 20℃; for 1 - 2h; Product distribution / selectivity;	86%
With sodium hydroxide In water

di-tert-butyl dicarbonate (24424-99-5) + pramipexole dihydrochloride (104632-25-9) + trifluoroacetic acid (76-05-1) → pramipexole(boc) trifluoroacetate

Conditions	Yield
Stage #1: di-tert-butyl dicarbonate; pramipexole dihydrochloride With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; for 3h; Stage #2: trifluoroacetic acid In water	422 mg

BOC-glycine (4530-20-5) + pramipexole dihydrochloride (104632-25-9) → 2ClH*C12H20N4OS

Conditions	Yield
Stage #1: BOC-glycine; pramipexole dihydrochloride With 4-methyl-morpholine; (benzotriazole-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate In dimethyl sulfoxide for 1h; Stage #2: With hydrogenchloride In methanol; water for 4h;	490 mg

BOC-glycine (4530-20-5) + pramipexole dihydrochloride (104632-25-9) + trifluoroacetic acid (76-05-1) → C17H28N4O3S*C2HF3O2

Conditions	Yield
Stage #1: BOC-glycine; pramipexole dihydrochloride With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In dimethyl sulfoxide for 1h; Stage #2: trifluoroacetic acid In water	721 mg

C25H25NO3S + pramipexole dihydrochloride (104632-25-9) + trifluoroacetic acid (76-05-1) → C35H40N4O2S2*C2HF3O2

Conditions	Yield
Stage #1: C25H25NO3S; pramipexole dihydrochloride With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In dimethyl sulfoxide for 16h; Stage #2: trifluoroacetic acid In water; acetonitrile	21 mg

C34H42N2O5S + pramipexole dihydrochloride (104632-25-9) + trifluoroacetic acid (76-05-1) → C44H57N5O4S2*C2HF3O2

Conditions	Yield
Stage #1: C34H42N2O5S; pramipexole dihydrochloride With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In dimethyl sulfoxide for 0.666667h; Stage #2: trifluoroacetic acid In water; acetonitrile	38 mg

Upstream product

• 1001648-71-0 (6S,7S)-2-amino-7-hydroxy-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole 
• 104632-26-0 pramipexole 
• 106006-83-1 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole 
• 104617-50-7 N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)acetamide hydrobromide 
• 27514-08-5 N-(4-oxocyclohexyl)acetamide 
• 106092-09-5 (S)-4,5,6,7-tetrahydrobenzo[d]thiazol-2,6-diamine 
• 106006-84-2 (S)?2?amino?6?propionamido?4,5,6,7?tetrahydrobenzothiazole 
• 873431-80-2 (S)-4,5,6,7-tetrahydro-benzothiazole-2,6-diamine tartrate trihydrate 
• 113030-24-3 2-amino-6-oxo-4,5,6,7-tetrahydrobenzothiazole 
• 4746-97-8 cyclohexanedione monoethylene ketal 
• 144810-01-5 1,4-cyclohexanedione-1-ethylene acetal 4-trimethylsilyl enol ether 
• 159015-33-5 2-amino-6-(ethylenedioxy)-4,5,6,7-tetrahydrobenzothiazole 
• 404892-23-5 2-Acetylamino-6-oxo-4,5,6,7-tetrahydrobenzothiazole 
• 1265141-51-2 (S)-t-butyl-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl(propyl)carbamate 

Downstream Products

• 104632-26-0 pramipexole 
• 191217-81-9 pramipexole dihydrochloride monohydrate 

Related news

Validated chiral liquid chromatographic method for the enantiomeric separation of Pramipexole dihydrochloride (cas 104632-25-9) monohydrate08/19/2019

A chiral liquid chromatographic method was developed for the enantiomeric resolution of Pramipexole dihydrochloride monohydrate, (S)-2-amino-4,5,6,7-tetra-hydro-6-(propylamino) benzothiazole dihydrochloride monohydrate, a dopamine agonist in bulk drugs. The enantiomers of Pramipexole dihydrochlo...detailed

Pramipexole dihydrochloride (cas 104632-25-9) loaded chitosan nanoparticles for nose to brain delivery: Development, characterization and in vivo anti-Parkinson activity08/18/2019

In the current study, Pramipexole dihydrochloride loaded chitosan nanoparticles (P-CNs) were prepared for Parkinson’s disease via nose to brain pathway by ionic gelation method. Optimized P-CNs with chitosan and sodium tripolyphosphate (6:1 v/v) exhibited particle size and entrapment efficiency...detailed

Relevant articles and documents

Preparation method of pramipexole

The invention discloses a preparation method of pramipexole. The method comprises the following steps: adding (S)-2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole into tetrahydrofuran, and carrying out a reduction reaction by using a sodium borohydride/boron trifluoride complex, wherein a molar ratio of (S)-2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole to sodium borohydride to boron trifluoride complex is 1:1:2-1:3:4; and separating to obtain a target product (S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole. The method provided by the invention has the advantages that the required raw materials are simple and easily available, the reaction conditions are mild, the use amount of the sodium borohydride/boron trifluoride complex is greatly reduced compared with theprior art, the reaction safety is greatly improved while the cost is saved, and the yield and the purity are higher, so that the method is suitable for industrial production.

Industrial preparation method for pramipexole and hydrochloride thereof

The invention relates to a preparation method for S-(-)pramipexole. The method comprises the following steps: (1) dissolving S-(-)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole in a mixed solvent, carrying out stirring, adding a basic catalyst and n-propyl p-toluenesulfonate, carrying out heating after completion of addition, then carrying out a stirring reaction, and carrying out filtering and drying after completion of the reaction so as to obtain white S-(-)pramipexole p-toluenesulfonate solid; and (2) adding S-(-)pramipexole p-toluenesulfonate into an aqueous solution of salt, adding an inorganic base under stirring, carrying out stirring at room temperature after completion of addition, and carrying out filtering and drying so as to obtain a white S-(-)pramipexole solid, wherein no organic solvent is used in the step (2).

Convenient N-Alkylation of amines using an effective magnetically separable supported ionic liquid containing an anionic polyoxometalate

Abstract: An effective synthesis of anion-exchanged supported ionic liquid using magnetically separable nanoparticles and its catalytic effect on N-alkylation reactions is described. Anionic polyoxometalate derivative was used in the anion-exchange step in catalyst design. The catalytic system can be easily separated from the reaction mixture with external magnetic field and recycled in subsequent reactions. In order to evaluate catalyst repeatability, N-alkylation of some more amines such as Aniline, 4-aminobenzenesulfonamide, 4-methoxyaniline, 2-aminopyrimidin and 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine in the presence of recoverable catalyst was successfully examined in this article. In addition, pramipexole dihydrochloride as an active pharmaceutical ingredient was successfully synthesized using the catalytic system. The structure of catalyst was determined by infrared spectroscopy, X-ray powder diffraction, and scanning electron microscope techniques. The structure of organic products was determined by 1H NMR, 13C NMR, infrared and Mass spectroscopy. Graphical Abstract: [Figure not available: see fulltext.]