29216-28-2

Basic information

• Product Name: MEQUITAZINE
• Synonyms: 10H-Phenothiazine, 10-(1-azabicyclo[2.2.2]oct-3-ylmethyl)- (9CI);Nipolazin;NSC 303612;Phenothiazine, 10-(3-quinuclidinylmethyl)- (8CI);Quitadrill;10-(1-Azabicyclo[2.2.2]octan-3-ylmethyl)-10H-phenothiazine;10-(Quinuclidin-3-ylmethyl)-10H-phenothiazine;MQ-A-88
• CAS NO: 29216-28-2
• Molecular Formula: C₂₀H₂₂N₂S
• Molecular Weight: 322.47
• EINECS: 249-521-7
• Product Categories: Heterocyclic Compounds;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 29216-28-2.mol

Chemical Properties

• Melting Point: 143-145°C
• Boiling Point: 469.4 °C at 760 mmHg
• Flash Point: 237.7 °C
• Appearance: White solid
• Density: 1.1330 (rough estimate)
• Refractive Index: 1.5800 (estimate)
• Storage Temp.: Refrigerator
• PKA: 10.43±0.33(Predicted)
• Water Solubility: Insoluble in water
• Merck: 14,5864
• CAS DataBase Reference: MEQUITAZINE(CAS DataBase Reference)
• NIST Chemistry Reference: MEQUITAZINE(29216-28-2)
• EPA Substance Registry System: MEQUITAZINE(29216-28-2)

Safety Data

• RIDADR: UN 2811 6.1/PG III
• RTECS: SP5080000
• HazardClass: 6.1
• PackingGroup: III
• Hazardous Substances Data: 29216-28-2(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

Originator

Primalan,Berk,UK,1976

Uses

It is an antihistamine

Manufacturing Process

30 g of phenothiazine were added, all at once, to a suspension of 6 g of sodium amide in 240 ml of anhydrous xylene. The mixture was agitated and heated to reflux. When evolution of ammonia ceased (5 hours), 15 g of 3- chloromethyl-quinuclidine hydrochloride were added portionwise over a period of 50 minutes and reflux was then maintained for 22 hours. After cooling to room temperature, 250 ml of distilled water and 250 ml of ethyl acetate were added to the reaction mixture. The aqueous phase was decanted and extracted twice with a total of 250 ml of methyl acetate. The combined organic extracts were extracted three times with a total of 750 ml of a 10% aqueous solution of tartaric acid. The combined acid solutions were treated with 5 g of animal charcoal, filtered and rendered alkaline on an ice bath with 96 ml of 10 N aqueous caustic soda. The oil which separated was extracted three times with a total of 1.500 ml of ethyl acetate. The combined organic extracts were washed to neutrality by washing twice with a total of 1 liter of distilled water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure on a water bath at 45°C. 17 g of oil were obtained which was purified by chromatography on an inert alumina column. 13.3 g of crystallized product were obtained. 10-(3-Quinuclidinyl-methyl)-phenothiazine having a MP of 130°C to 131°C was obtained by recrystallization in boiling acetonitrile. The 3-chloromethyl-quinuclidine hydrochloride used as starting material in this process can be obtained as described by Grob and coll., Helv. Chim. Acta, 37 (1954),1689.

Therapeutic Function

Antihistaminic

InChI:InChI=1/C20H22N2S/c1-3-7-19-17(5-1)22(18-6-2-4-8-20(18)23-19)14-16-13-21-11-9-15(16)10-12-21/h1-8,15-16H,9-14H2

Synthetic route

dehydromequitazine (151129-13-4) → mequitazine (29216-28-2)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; under 760.051 Torr; for 24h;	91%
With hydrogen; palladium 10% on activated carbon In methanol; toluene at 20℃; under 75007.5 Torr; for 24h;	91%

(E)-10-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)phenothiazine (151129-15-6) → mequitazine (29216-28-2)

Conditions	Yield
With triethylsilane; trifluoroacetic acid at 0 - 32℃; for 2.5h; Inert atmosphere; Large scale;	85%
With hydrogen; acetic acid; palladium-carbon In methanol; water
With hydrogen; acetic acid; palladium-carbon In methanol; water

10H-phenothiazine (92-84-2) + 3-chloromethyl-quinuclidine; hydrochloride (86014-80-4) + tartaric acid (87-69-4) → mequitazine (29216-28-2)

Conditions	Yield
In 5,5-dimethyl-1,3-cyclohexadiene; acetic acid methyl ester; water; ethyl acetate

mequitazine (29216-28-2) → 10-(1-azabicyclo[2.2.2]oct-3-yl-methyl)-10H-pheno-thiazine hydrochloride

Conditions	Yield
With hydrogenchloride In water

mequitazine (29216-28-2) → 10-(1-azabicyclo[2.2.2]oct-3-yl-methyl)-10H-pheno-thiazine sulfoxide (40765-34-2)

Conditions	Yield
With hydrogenchloride; sodium nitrite In water at 20℃;

mequitazine (29216-28-2) + glycolamide (598-42-5) → 2C20H22N2S*C2H5NO2

Conditions	Yield
In acetone for 0.5h; Milling;

mequitazine (29216-28-2) + (2E)-but-2-enedioic acid (110-17-8) → C20H22N2S*C4H4O4

Conditions	Yield
at 180℃; for 6h;

mequitazine (29216-28-2) + succinic acid (110-15-6) → C20H22N2S*C4H6O4

Conditions	Yield
In acetone for 0.5h; Milling;

mequitazine (29216-28-2) + glycolic Acid (79-14-1) → C20H22N2S*C2H4O3

Conditions	Yield
With water for 0.5h; Milling;

Upstream product

• 92-84-2 10H-phenothiazine 
• 86014-80-4 3-chloromethyl-quinuclidine; hydrochloride 
• 87-69-4 tartaric acid 
• 151129-13-4 dehydromequitazine 
• 151129-15-6 (E)-10-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)phenothiazine 

Downstream Products

• 40765-34-2 10-(1-azabicyclo[2.2.2]oct-3-yl-methyl)-10H-pheno-thiazine sulfoxide 

Relevant articles and documents

Expedient synthesis of mequitazine an antihistaminic drug by palladium catalyzed allylic alkylation of sodium phenothiazinate

A short and straightforward synthesis of the antihistaminic drug mequitazine is reported, based on an efficient palladium catalyzed allylic alkylation of 1-aza-bicyclo[2.2.2]oct-2-en-3-ylmethyl acetate using sodium phenothiazinate in mild conditions.

Method for industrially producing mequitazine

The invention relates to a method for industrially producing mequitazine. The method comprises the steps that under the nitrogen condition, trifluoroacetic acid and triethyl silicane are mixed, (E)-10-(1-aza bicyclic[2,2,2]cyn-3-methylene)-phenothiazine is added in batches for a reaction, water and alkali are added in sequence, extraction is performed, and an organic phase is acidified, crystallized and filtered. The method is mild in reaction condition, no high temperature or high energy dissipation is caused, solvents can be recycled, the cost is reduced, and discharge of waste is reduced.

NOVEL QUINUCLIDINE DERIVATIVE USEFUL IN THE PREPARATION OF MEQUITAZINE

The invention relates to a 1-aza-bicyclo[2.2.2]oct-2-en-3-ylmethyl acetate of the formula (I), wherein said compound is useful as a synthesis intermediate for the production of mequitazine.

Highly pure phenothiazine compound, production method thereof, production method of intermediate therefor, and hydrate and novel crystal as starting materials for the intermediate

According to the method of the present invention, an alkali metal compound, dimethyl sulfoxide, trimethyloxosulfonium halide and 3-quinuclidinone are added in a specific order to give the following compound [II]. This compound is, without treatment or isolation, directly reacted with an alkali metal salt of phenothiazine to give the following compound [III], from which the following compound [I] is obtained. During the production of compound [I], a by-produced acidic gas is removed and water is added to ensure industrial, safe and efficient production of compound [I] at a constantly high yield. Inasmuch as the present invention enables production of the following highly pure compound [A] by eliminating hydrogen halide of compound [I] in glyme in the presence of at least one kind of a base selected from potassium hydroxide and potassium alkoxide, compound [A] having a high purity of not less than 85 mol % can be provided.

Phenothiazine derivative

Phenothiazine derivatives are described of the formula SPC1 In which X1 and X2, which may be the same or different, are H, R, F, Cl, Br, OR, CN, --COR, CH3, --S--R, --SOR, --SO2 R or --SO2 N(CH3)2, where R is an alkyl group having from 1 to 4 carbon atoms, and the quinuclidine ring is substituted by the group --(CH2)x -- in the 2- or 3- position, x being 1 or 2 when said group is substituted in the 2-position and being 0 or 1 when said group is substituted in the 3-position (because of electronic hindrance), and their acid addition and quaternary ammonium salts, have valuable pharmacological properties. In particular, these compounds have anti-histaminic, anti-cholinergic, adrenolytic, neuro-sedative, tranquillizing and/or spasmolytic properties. These compounds are prepared by condensing an appropriate phenothiazine with a quinuclidine derivative of the formula SPC2 In which x has the above-stated meaning and Z is a halogen atom or a reactive ester group.