Gefitinib, US 8350029, CIPLA, PATENT

US 8350029

http://www.google.co.in/patents/US8350029

Inventors	Dharmaraj Ramachandra Rao, Rajendra Narayanrao Kankan, Srinivas Laxminarayan Pathi,
Original Assignee	Cipla Limited

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CIPLA Limited, Mumbai, India

Gefitinib is an anilinoquinazoline which is useful in the treatment of a certain type of lung cancer (non-small cell lung cancer or NSCLC) that has not responded to chemotherapy. The chemical name for gefitinib is 4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline. Its structural formula is:

The earliest known synthesis of gefitinib was first disclosed in the patent application WO 96/33980. The synthetic method employed is depicted in the following reaction scheme 1.

The process involves selective demethylation of 6,7-dimethoxy quinazoline-4-one using methanesutfonic acid and L-methionine to get its 6-hydroxyl derivative, which is protected by acetylation. The acetoxy compound is chlorinated and condensed with chloro-fluoroaniline. Hydrolysis of the acetoxy compound followed by etherification with 3-morpholinopropyl chloride gives crude gefitinib which is purified by column chromatography. The process suffers from many disadvantages as it involves several protection and deprotection steps. The selective demethylation using methionine results in isomeric impurities and has to be purified or else the impurity carries over to subsequent steps in the preparation of gefitinib making it more difficult to isolate a pure product. The process also leads to formation of an N-alkylated impurity at the final stage which must be separated by column chromatography to obtain gefitinib.
Several other approaches are also described in the literature to make gefitinib.
WO 2004/024703 discloses a process for the preparation of gefitinib starting from 3-hydroxy-4-methoxy benzonitrile which involves condensation of 3-hydroxy-4-methoxy benzonitrile with morpholino propyl chloride, nitration, reduction with sodium dithionite to amino compound, hydrolysis of nitrile to amide, cyclisation in the presence of formamide to obtain quinazoline, chlorination with phosphorous oxychloride and finally condensation with chloro-fluoro aniline to obtain gefitinib. The process involves multiple steps and hence is time consuming.
WO 2005/023783 discloses a process for the manufacture of gefitinib starting from 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile. The process involves a rearrangement reaction of 3-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)3,4-dihydroqunazoline-4-imine. The process is not feasible industrially, as the basic raw material is not readily available on a commercial scale and involves the use of excess 3-chloro-4-fluoroaniline which is expensive. A further draw back of the process is in the isomerization of the 4-imine compound which requires anhydrous conditions at high temperature for a longer duration of 96 hours. All the problems associated with this prior art process are overcome by the novel process of the present invention.
WO2005/070909 discloses a process for the preparation of gefitinib starting from isovanillin as depicted in scheme 2

The WO' 909 process has disadvantages as it forms cis-trans geometrical isomers of the oxime, which have different reactivities. Furthermore, the process uses a large excess of acetic anhydride to convert the oxime to the nitrile at higher temperature.
The patent applications 901/CHE/2006 and 903/CHE/2006 disclose another route for preparing gefitinib starting from isovanillin. The process involves formation of a formamido compound [N′-[2-cyano-4-{3-(4-morpholinyl)propoxy}phenyl]-N,N-dimethyl formamide], which is unstable and may result in undesired impurities in the final condensation with 3-chloro-4-fluoro aniline, thereby making the process less feasible on an industrial scale.
The processes disclosed in the prior art are cumbersome. Therefore, there exists a need for a more economical and efficient method of making gefitinib which is suitable for industrial scale-up.
The process of the present invention avoids use of reagents such as sodium dithionite, acetic anhydride and allows substantial reduction in the number of problems associated with these reagents.

 

Process for Preparation of Gefitinib

Gefitinib, 66, is used in the treatment of certain types of lung cancer, and a number of methods are reported for its synthesis. These are described as cumbersome and can require excessive amounts of reagents or involve difficult purification methods. Some processes use reagents such as sodium dithionite or Ac₂O, and these are said to create problems. This patent discloses two routes for the synthesis of 66 that are claimed to avoid such problems. The first route, shown in Scheme 22, is the subject of the claims of the patent and starts with the nitration of isovanillin 57ain HOAc to give 57b that is recovered in 65% yield. Treatment of 57b with 58 produces 59a that is isolated in 92% yield, and this is then oxidised with H₂O₂ to form the acid 59b that is isolated in 86% yield. Reduction of the nitro group is then carried out to give 60, and there are three methods described for this reaction. The first is catalytic hydrogenation with Pd/C that gives a 90% yield of60. The reaction pressure is reported as being 5–6 kg, a common term in India used as short-hand for the pressure unit of kg/m². Reduction using H₂NNH₂ in the presence of FeCl₃, Al₂O₃, and charcoal gives a 83.6% yield of 60. In a hydrogen-transfer reaction with HCO₂NH₄ and Pd/C compound, 60 is recovered in 84.5% yield. The cyclisation of 60 to form 61 is carried out in a Niementowski reaction using HCO₂NH₄ and HCO₂NH₂, and the product is recovered in 90% yield. Reaction of 61 with SOCl₂ produces 62, and this is isolated in 95% yield. Only the main reagents are shown in the scheme, and workup details are omitted.

Scheme 22. ^a

^aReagents and conditions: (a) (i) HNO₃, HOAc, −5 °C; (ii) 30 °C, 12 h. (b) K₂CO₃, MeCN, reflux, 4 h. (c) (i) 30% NaOH/MeOH, 45 °C; (ii) add 35% H₂O₂ over 4 h, 45 °C, pH 11. (d) Pd/C, H₂, EtOAc, 40 °C, 4 h. (e) HCO₂NH₄, HCO₂NH₂, 180 °C, 4 h. (f) SOCl₂, DMF, reflux, 8 h.

In the next stage of the synthesis, shown in Scheme 23, compound 62 is reacted with morpholine63 to give 64 in 85% isolated yield. In the final step 64 is reacted with 65 to produce 66 that is recovered in 70% yield (purity not reported).

Scheme 23. ^a

^aReagents and conditions: (a) (i) 75 °C, 8 h; (ii) cool to rt, add H₂O; (iii) separate extract in DCM, H₂O wash, dry, evaporate. (b) MeOH, 30 °C, 0.25 h; (ii) add 65, reflux 6 h; (iii) add HCl at 20 °C; (iii) <10 °C, 0.5 h; (iv) filter, MeOH wash; (v) dissolve in PhMe/MeOH, concentrate; (vi) cool <10 °C, filter, PhMe wash, dry.

The patent also describes an alternative route to 66 that is outlined in Schemes 24 and 25although it is not covered by the patent claims. The route starts with the oxidation of 57a using H₂O₂ to give the acid 67a that is esterified to form 67b that is isolated in 83% yield. Nitration of67b with HNO₃ in HOAc produces 68a that is isolated in 74% yield and then reduced to 68b over Pd/C. The amine 68b is recovered in 93% yield and then reacted with 69 to give the quinazoline70a that is recovered in 92% yield and then acetylated to form 70b. There is no example describing this acetylation nor are there any for the remaining steps of this route shown in Scheme25, and the reactions are just generally referred to in the text.

Scheme 24. ^a

^aReagents and conditions: (a) (i) 30% NaOH/MeOH, 45 °C; (ii) add 35% H₂O₂ over 3 h, 45 °C, pH 11. (b) 10% HCl/MeOH, reflux, 6 h. (c) 70% HNO₃, HOAc, −5 °C, 18 h. (d) Pd/C, H₂, EtOAc, 40 °C, 4 h. (e) MeOH, reflux, 10 h. (f) No details.

Scheme 25. ^a

^aReactions: (a) Chlorination. (b) Condensation. (c) Hydrolysis. (d) Coupling.

The examples report experiments carried out on a reasonable scale with some producing up to 200 g of products. Unfortunately, there are no details of the purity of any of the intermediates, and although the patent states that the desired final product 66 is purified by acid/base treatment or crystallisation, there are no details provided.

Advantages

The process does avoid the use of some difficult reagents used elsewhere, but whether the process gives a higher-purity product than alternatives is not clear.

scheme 3.

scheme 4.

EXAMPLE 1 Preparation of 4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)-quinazoline (gefitinib) (Formula I)Methanol (1200 ml) and 6-(3-morpholino propoxy)-7-methoxy-4-chloro quinazoline (200 gm) were stirred for 15 minutes at 25-30° C., then a solution of 4-fluoro-3-chloroaniline in methanol (213 gm in 400 ml) was charged and refluxed for 6 hours. The reaction mass was cooled to 15-20° C., hydrochloric acid (40 ml) was added drop wise, and stirred at 5-10° C. for 30 minutes. The solid obtained was filtered and washed with chilled methanol (150 ml). The solid was dissolved in a mixture of toluene (30 volume) and methanol (5 volume), the reaction mass was concentrated to half the volume and cooled to 5-10° C. The solid obtained was filtered, washed with toluene (200 ml) and dried at 45-50° C. to yield the title compound (183 gm, 70% yield).
EXAMPLE 2 Preparation of 6-(3-morpholino propoxy)-7-methoxy-4-chloroquinazoline (Formula VII)DMF (3 lt), 6-(3-chloropropoxy)-7-methoxy-4-chloro quinazoline (200 gm) and morpholine (210 gm), were heated to 70-75° C. for 6-8 hours. The reaction mass was cooled to room temperature, and methylene chloride (2.5 lt) and water (2.5 lt) were charged. The layers separated and the aqueous layer extracted with methylene chloride twice (500 ml). The combined methylene chloride layer was washed with water, dried over sodium sulphate (10 gm) and concentrated completely at 35-40° C. to yield the title compound (200 gm, 85% yield).
EXAMPLE 3 Preparation of 6-(3-chloropropoxy)-7-methoxy-4-chloroquinazoline (Formula VI)6-(3-chloropropoxy)-7-methoxyquinazoline-4-one (400 gm), thionyl chloride (3.2 lt) and DMF (100 ml) were refluxed for 7-8 hours. Thionyl chloride was distilled off completely under reduced pressure below 45° C. Methylene chloride (2.5 lt) and water (1.5 lt) were charged, stirred for 30 minutes at room temperature and the layers separated. The aqueous layer was extracted twice with methylene chloride (500 ml), the combined methylene chloride layer was washed with 1% sodium bicarbonate solution (1 lt), dried over sodium sulphate (20 gm) and concentrated under reduced pressure at 35-40° C. The residue was stirred with isopropyl alcohol (400 ml) at 40-45° C. for 1 hour, cooled to 0-5° C., the solids filtered, washed with chilled isopropyl alcohol (200 ml) and dried under vacuum at 45° C. to yield the title compound (406 gm, 95% yield).
EXAMPLE 4 Preparation of 6-(3-chloropropoxy)-7-methoxyquinazoline-4-one (Formula V)2-amino-4-methoxy-5-(3-chloropropoxy)benzoic acid (450 gm), formamide (2250 ml) and ammonium formate (200 gm) were heated to 170-180° C. for 3-4 hours. The reaction mass was concentrated under reduced pressure at 140-150° C. The residue was stirred in methanol (1000 ml) at 45-50° C. and cooled to 5-10° C. The solid obtained was filtered to yield the title compound (420 gm, 90% yield).
EXAMPLE 5 Preparation of 2-amino-4-methoxy-5-(3-chloropropoxy)benzoic acid (Formula IV) a) Preparation of 3-(3-chloropropoxy)-4-methoxy-6-nitrobenzoic acidMethanol (4 lt), 3-(3-chloropropoxy)-4-methoxy-6-nitro benzaldehyde (560 gm) and 30% methanolic NaOH solution (5 ml) were heated to 45° C. To this reaction mass 35% of H₂O₂ solution (1200 ml) was added drop wise in 3-4 hours maintaining a pH of 10.5-11.5 with 30% methanolic NaOH solution. The reaction mass was quenched into ice water (10 kg) and the pH adjusted to 2.0-3.0 using hydrochloric acid. The solid obtained was filtered, washed with 50% aqueous methanol (500 ml) and dried at 45-50° C. to yield the title compound (510 gm, 86% yield).
bi) Preparation of 2-amino-4-methoxy-5-(3-chloropropoxy)benzoic acid—Using Hydrogen GasEthyl acetate (3 lt), Pd/C (50 gm) and 3-(3-chloropropoxy)-4-methoxy-6-nitrobenzoic acid (500 gm) were hydrogenated under a hydrogen pressure of 5-6 kg at 35-40° C. for 3-4 hours. The reaction mass was filtered and the clear filtrate was distilled under reduced pressure at 45-50° C. To the residue, hexane (1 lt) was charged, stirred at room temperature, the solids filtered and dried at 45-50° C. to yield the title compound (403 gm, 90% yield).
(bii) Preparation of 2-amino-4methoxy-5-(3-chloropropoxy)benzoic acid—Using Hydrazine Hydrate3-(3-chloropropoxy)-4-methoxy-6-nitrobenzoic acid (100 gm), hydrazine hydrate (50 gms), neutral alumina (20 gms), charcoal (10 gms), water (50 ml) and methanol (500 ml) were mixed together. The reaction mass was heated to 50° C. A solution of ferric chloride (2 gms, 0.012M) in 50 ml methanol was introduced slowly at 55-60° C. The reaction mass was filtered over hyflo and the clear filtrate evaporated. The residue obtained was dissolved in 1.0-lit ethyl acetate, washed organic extract with water, evaporated to obtain title compound. (75 gms, 83.6%)
(biii) Preparation of 2-amino-4-methoxy-5-(3-chloropropoxy)benzoic acid—Using Ammonium Formate3-(3-chloropropoxy)-4-methoxy-6-nitro benzoic acid (165 gms), 5% Paladium on carbon (16.5 gms) and DMF (0.66 lit) were mixed together. The reaction mass was heated to 40° C. Ammonium formate (82.5 gms) was charged in lots maintaining temperature below 50° C. The temperature of reaction mass slowly raised to 70° C. and maintained for 2 hours. The reaction mass was cooled to 30° C. and catalyst was removed by filtration and the clear filtrate evaporated. The residue was dissolved in ethyl acetate (0.825 lit), washed with water and evaporated to yield the title compound. (125 gms, 84.5%)
EXAMPLE 6 Preparation of 3-(3-chloropropoxy)-4-methoxy-6-nitro benzaldehyde (Formula III)5-nitro isovanillin (500 gm), acetonitrile (3.5 lts), K₂CO₃ (750 gm) and chlorobromopropane (780 gm) were refluxed for 4 hours. The reaction mass was filtered hot, washed with acetonitrile (1 lt) and the filtrate was distilled off to remove solvent. The residue was dissolved in methylene chloride (4 lt) and washed with water. Water (3 lt) was charged to the methylene chloride layer, the pH adjusted to 7.0 to 7.5 with acetic acid, the methylene chloride layer separated, dried over sodium sulphate (50 gm) and distilled out completely under reduced pressure below 40° C. The residue was stirred with 2 volumes of n-Hexane at 40-45° C., cooled slowly to 0-5° C., the solids filtered, washed with n-Hexane (250 ml) and dried at 40-45° C. to yield the title compound (638 gm, 92% yield).
EXAMPLE 7 Preparation of 5-nitro isovanillin (Formula II)Isovanillin (500 gm) and acetic acid (1750 ml) were cooled to −5 to 0° C. To this solution, nitric acid (750 ml) was charged slowly at −5 to 0° C. with stirring. The temperature of the reaction mass was slowly raised to 25-30° C. and maintained for 12 hours. The reaction mass was quenched into ice water (4 kg), the solids filtered and washed with water (2 lt). The solids were stirred with a 1% sodium bicarbonate solution (1 lt), filtered and dried at 45-50° C. The solid was dissolved in 6 volumes of ethyl acetate, ethyl acetate was distilled off up to half the volume and 3 volumes of n-Hexane were charged slowly at 45-50° C. The reaction mass was cooled slowly to 0-5° C., maintained for 1 hour, the solids filtered, washed with 0.5 volumes of 1:1 mixture of ethyl acetate:n-Hexane and dried at 45-50° C. to yield the title compound (423 gm, 65% yield).
EXAMPLE 8 Preparation of Methyl-2-hydroxy-3-methoxy benzoate (Formula VIII) a) Preparation of 3-hydroxy-4-methoxy benzoic acidMethanol (350 ml), isovanillin (50 gm) and 30% methanolic sodium hydroxide solution (1 ml), were heated to 45° C. To this solution, 35% hydrogen peroxide solution (107 ml) was charged slowly maintaining pH at 10.5 to 11.5 using methanolic sodium hydroxide solution over a period of 2-3 hours. The reaction mass was quenched into chilled water (1 lt) and the pH adjusted to 2-3 using hydrochloric acid. The solids were filtered, washed with 50% aqueous methanol (50 ml) and dried at 45-50° C. to yield 3-hydroxy-4-methoxy benzoic acid.
b) Preparation of Methyl-2-hydroxy-3-methoxy benzoateThe solid obtained in step a), was refluxed with 10% methanolic hydrochloric acid solution (250 ml) for 6 hours. The reaction mass was quenched into chilled water (1 lt) and repeatedly extracted with methylene chloride (250 ml). The combined methylene chloride layer was washed with water (100 ml×2) and methylene chloride distilled out completely at 35-40° C. The residue was stirred in hexane (1.50 ml), at 25-30° C. The solid obtained was filtered, washed with: hexane (25 ml) and dried at 40-45° C. to yield the title compound (50 gm, 83% yield).
EXAMPLE 9 Preparation of Methyl-5-hydroxy-4-methoxy-2-nitro benzoate (Formula IX)Methyl-2-hydroxy-3-methoxy benzoate (50 gm) and acetic acid (175 ml) were cooled to 0-5° C. To this solution, 70% nitric acid solution (75 ml) was charged slowly at 0-5° C. under stirring and the reaction mass was further stirred for 18 hours. The reaction mass was quenched into chilled water (800 ml) and extracted repeatedly with methylene chloride (400 ml). The combined methylene chloride layer was washed with water, followed by 1% potassium carbonate solution (100 ml), dried over sodium sulphate and methylene chloride distilled off completely at 35-40° C. The residue was dissolved in 10% aqueous methanol (250 ml). The filtrate was gradually cooled to 0-5° C. and maintained for 1 hour. The solid obtained was filtered, washed with 10% aqueous methanol (100 ml) and dried at 40-45° C. to yield the title compound (46 gm, 74% yield).
EXAMPLE 10 Preparation of Methyl-2-amino-5-hydroxy-4-methoxy benzoate (X)Ethyl acetate (300 ml), methyl-5-hydroxy-4-methoxy-2-nitro benzoate (50 gm) and 10% palladium/carbon (5 gm) were hydrogenated under a hydrogen gas pressure of 5-6 kg for 4 hours. The reaction mass was filtered to remove catalyst. The filtrate was distilled off to remove solvent. The residue obtained was stirred in n-hexane (100 ml) at 0-5° C. The solid obtained was filtered and washed with n-hexane (25 ml) to yield the title compound (40 gm, 93% yield).
EXAMPLE 11 Preparation of 6-hydroxy-7-methoxy-quinazoline-4-one (formula XI)Methyl-2-amino-5-hydroxy-4-methoxy benzoate (50 gm), methanol (400 ml) and formamidine acetate (30 gm) were refluxed for 10 hours. The reaction mass was gradually cooled to 5-10° C. and stirred for 1 hour. The solid obtained was filtered and washed with methanol (150 ml) and dried at 50-55° C. to yield the title compound (45 gm, 92% yield).

Cited Patent	Filing date	Publication date	Applicant	Title
US6297257	17 Dec 1998	2 Oct 2001	Zambon Group S.P.A.	Benzazine derivatives phosphodiesterase 4 inhibitors
EP1477481A1	28 Jan 2003	17 Nov 2004	Ube Industries, Ltd.	Process for producing quinazolin-4-one derivative
IN901CHE2006A				Title not available
IN903CHE2006A				Title not available
WO1996033980A1	23 Apr 1996	31 Oct 1996	Zeneca Limited	Quinazoline derivatives
WO2004024703A1	9 Sep 2003	25 Mar 2004	Astrazeneca Ab	Process for the preparation of 4- (3’-chloro-4’-fluoroanilino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline
WO2005023783A1	1 Sep 2004	17 Mar 2005	Astrazeneca Ab	Process for the manufacture of gefitinib
WO2005070909A1	27 Jul 2004	4 Aug 2005	Natco Pharma Limited	An improved process for the preparation of gefitinib
WO2008125867A2	16 Apr 2008	23 Oct 2008	Cipla Limited	Process for the preparation of gefitinib

/////////Gefitinib, US 8350029, CIPLA

PATENT, US 8344136, PHF S.A., Brinzolamide

US 8344136

http://www.google.co.in/patents/US8344136

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PHF S.A., Lugano, Switzerland

 

Inventors	Alessandro Falchi, Ottorino De Lucchi, Andrea Castellin
Original Assignee	Phf S.A.

Process for the Preparation of Brinzolamide

Brinzolamide is a carbonic anhydrase II inhibitor, used to lower intraocular pressure and glaucoma. It is sold by Alcon under the name of Azopt, as 1% ophthalmic suspension.
EP 527801 claims Brinzolamide and describes a process to prepare it in 14 steps starting from 3-acetylthiophene (scheme 1). It is a synthesis typical of medicinal chemistry not applicable at industrial level, for which no specific preparations are described, because Brinzolamide is not among the preferred compounds of the invention.

This synthesis is not very efficient because requires the change of the oxidation status of the functional group in position 4 for three times; indeed this is first reduced with Sodium borohydride (step (5)) to α-bromoalcohol and then oxidized with Sodium dichromate (step (11)), a very toxic reagent. This sequence is necessary to obtain the cyclization (6), which brings only to degradation products on the ketone, and which requires a complex and not much efficient procedure as far as the quality and yield of the isolated product is concerned. The second reduction (12) occurs in the presence of (+)-β-chlorodiisopinocamphenylborane, an expensive enantioselective reducing agent, with a stoichiometric excess of 5:1, which requires reaction conditions not easily achievable at industrial scale (3 days of reaction at −22° C., difficult work up and chromatography) to isolate the product.
It can be inferred from the patent that there is the possibility to fix the stereogenic centre through selective crystallization of the salt of a chiral acid as di-p-toluoyl-D-tartaric acid, expensive resolution agent, with consequent loss of at least half of the substrate.
EP 617038 describes a process for the preparation of Brinzolamide and its analogues starting from 3-acetyl-2,5-dichlorothiophene (scheme 2).

The reduction (6) with (+)-β-chlorodiisopinocamphenylborane and the cyclization (7) bring to the optically active alcohol 2H-thieno[3,2-e]-1,2-thiazin-4-ol, 6-chloro-3,4-dihydro-, 1,1-dioxide, (4S)-. The formation of a product enriched with one of the enantiomer is too early in the synthesis, with a consequent risk of racemisation during the following steps, while the reduction would be more efficient if performed on a more advanced intermediate. The disadvantages of the use of the enantioselective reducing agent (6) and of the cyclization of the alcohol (7) are the same of the method described in Scheme 1. Another disadvantage is the alkylation (8) with 1-bromo-3-methoxypropane, that, in order to avoid the reaction of the oxydrilic group, is performed portionwise, with low temperatures and long reaction times.
The sulfonamide is introduced in position 6 through metallation with n-butyl lithium, an expensive raw material, and then with a reaction with sulphurous anhydride and hydroxylamino-O-sulphonic acid. The base should be used in substantial excess (2,3 eq.), because the oxydrilic group reacts with the first equivalent. In this case the protection of the oxydrilic group as described in Scheme 1 is not possible without running the risk of racemization of the substrate.
Lastly, the conversion of the secondary alcohol to the amine is difficult and requires the protection (10) of the primary sulfonamide with trimethyl orthoacetate, the activation (11) of the oxydrilic group with tosyl chloride and finally the substitution (12) of the tosyl group with ethylamine and at the same time the aminolysis of the protection of sulfonamide with the excess of ethylamine.
This synthesis is described in Org. Process Res. Dev. 3, 1999, 114, written by the R&D laboratories of Alcon. So it is reasonable to believe that this synthesis is used by Alcon at industrial level. Anyway, due to the low purity of the product obtained (97%), several crystallizations are needed to have a product of acceptable pharmaceutical grade.
U.S. Pat. No. 5,470,973 describes a variant of the synthesis in scheme 1, which involves an alternative preparation of the syntone 2H-thieno[3,2-e]-1,2-thiazin-4-ol, 6-chloro-3,4-dihydro-2-(3-methoxypropyl)-, 1,1-dioxide, (4S)- and the other analogues lacking chlorine in position 6 or the 3-methoxypropylic chain (scheme 3).

To introduce the chiral centre, firstly the oxidation (8) with dichromate is performed, and then the stereoselective reduction (9) with (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrol[1,2-c][1,3,2]oxazaborole are performed. The need of oxidizing first and then reducing was already commented in the description of the first synthetic path; the low enantiomeric excess (92%) is another disadvantage.
So it is evident the need of an alternative process for the preparation of Brinzolamide which can resolve the above mentioned technical problems.

OVERVIEW

 

Brinzolamide, 56, is used to treat glaucoma and can be synthesised by a 14-step route from acetylthiophene. This route is described as inefficient because of several changes of the oxidation state of one of the functional groups. Other routes have fewer steps but are still not very efficient. This patent describes a method for making compounds that are intermediates in the synthesis of56. The route is outlined in Schemes 20 and 21 and starts from the thiophene 49a or its chloro-derivative 49b (X = Cl). The first step is protection of the carbonyl group in 49a by reaction with 50to form 51a that is isolated in 87% yield. In the next step 51a is treated with K₂CO₃ to effect intermolecular cyclisation and formation of 52a. This can be obtained in 90% yield, or the reaction mixture can be treated with 53 without isolation of 52a to form 54a that is isolated 90% yield.

Scheme 20. ^a

^aReagents and conditions: (a) (i) TsOH, PhMe, reflux, 12 h; (ii) cool to rt, add Et₃N, separate; (iii) H₂O wash, evaporate. (b) (i) K₂CO₃, DMSO, 60 °C, 1 h; (ii) add H₂O/EtOAc, acidify to pH 7; (iii) separate, H₂O wash, evaporate. (c) (i) 60 °C, 8 h; (i) add H₂O/PhMe, separate; (iii)H₂O wash, evaporate.

The next stage is the introduction of the second sulphonamide group as shown in Scheme 21. This begins with treatment of 54a with BuⁿLi followed by addition of liquid SO₂. The intermediate reaction product is isolated as a solid and then treated with H₂NOSO₃H to form 54c that is recovered in 76% yield. The protective diol group is then removed by acid hydrolysis to give 55a in 97% yield. The conversion of 55a to 56 is not described in the patent, and reference to alternative syntheses of 56 indicate that this proceeds via asymmetric reduction of 56 to a hydroxy group that is then converted to the amine.

Scheme 21. ^a

^aReagents and conditions: (a) BuⁿLi, THF, −40 °C, 1 h; (ii) SO₂, −40 °C; (iii) warm to rt, evaporate; (iv) add H₂O, wash in DCM; (v) H₂NOSO₃H, NaOAc, H₂O, rt, 8 h; (vi) extract in EtOAc, wash in aq NaHCO₃, H₂O wash; (vii) evaporate. (b) (i) Aq HCl, PhMe, 80 °C, 16 h; (ii) separate, evaporate. (c) No details.

Compound 55a can be prepared by the same sequence of reactions shown in Schemes 20 and21 when starting from 49b. The yields of the corresponding intermediates are similar to or better than those reported for the method starting from 49a. The patent does not indicate the scale of the reactions, and the examples merely state the amounts of reactants used in terms of equivalents. The purity of the intermediates is not given, although ¹H NMR data are provided. The patent does not disclose how to obtain either of the starting materials, 49a or 49b, that are unlikely to be commercially available, and their synthesis will presumably add more steps to the synthesis of 56.

Advantages

The process provides an alternative route to the desired compound, but whether it is commercially viable and more efficient is not known.

Example 7 2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin]-6′-sulphonamide, 1′,1′-dioxide 9 (X=sulphonamide)

The desired compound is prepared according to general procedure 4 starting from 2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 5 with a yield of 76%.
¹H-NMR (300 MHz, DMSO-d₆): 8.05 (s, 2H), 7.59 (s, 1H), 4.16 (m, 2H), 4.07 (m, 2H), 3.87 (s, 2H), 3.4-3.3 (m, 4H), 3.21 (s, 3H), 1.81 (m, 2H).
LC-MS: [M+H]⁺=399.
Example 8 2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin]-6′-sulphonamide, 1′,1′-dioxide 9 (X=sulphonamide)

The desired compound is prepared according to general procedure 4 starting from 6′-chloro-2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 6 with a yield of 89%.
General Procedure 5 Hydrolisis of the Protective GroupThe compound of formula 5 is dissolved in toluene (10-20 volumes) and an aqueous solution of hydrochloric acid 2-12 N is added. The mixture is stirred at a temperature which can vary between 20° C. and 80° C. for a time between 2 and 16 ore, until complete hydrolysis. The phases are separated and the product 1 is isolated through distillation of the organic solvent under vacuum, obtaining a solid with a HPLC assay of 85-95% and a yield of 65-99%.
Example 9 4H-thieno[3,2-e]-1,2-thiazin-4-one, 2,3-dihydro-, 1,1-dioxide 1 (X and R=hydrogen)

The desired compound is prepared according to the general procedure 5 starting from 2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 3 with a yield of 66%.
¹H-NMR (300 MHz, DMSO-d₆): 8.90 (bt, 1H), 7.98 (d, 1H), 7.46 (d, 1H), 4.23 (d, 2H).
LC-MS: [M+H]⁺=204.
Example 10 4H-thieno[3,2-e]-1,2-thiazin-4-one, 6-chloro 2,3-dihydro-, 1,1-dioxide 1 (X=chlorine and R=hydrogen)

The desired compound is prepared according to general procedure 5 starting from 6′-chloro-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 4 with a yield of 95%.
¹H-NMR (300 MHz, DMSO-d₆): 9.08 (bs, 1H), 7.56 (s, 1H), 4.26 (d, 2H).
GC-MS: [M]^+•=237.
Example 11 4H-thieno[3,2-e]-1,2-thiazin-4-one, 2,3-dihydro-2-(3-methoxypropyl)-, 1,1-dioxide 5 (X=hydrogen)

The desired compound is prepared according to the general procedure 5 starting from 2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 5 with a yield of 97%.
¹H-NMR (300 MHz, DMSO-d₆): 8.05 (d, 1H), 7.49 (m, 1H), 4.58 (s, 2H), 3.3-3.1 (m, 7H), 1.73 (m, 2H).
LC-MS: [M+H]⁺=276.
Example 12 4H-thieno[3,2-e]-1,2-thiazin-4-one, 6-chloro 2,3-dihydro-2-(3-methoxypropyl)-, 1,1-dioxide 5 (X=chlorine)

The desired compound is prepared according to the general procedure 5 starting from 6′-chloro-2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 6 with a yield of 99%.
¹H-NMR (300 MHz, DMSO-d₆): 7.59 (s, 1H), 4.50 (s, 2H), 3.3-3.2 (m, 4H), 3.18 (s, 3H), 1.74 (m, 2H).
LC-MS: [M+H]⁺=310.
Example 13 2H-thieno[3,2-e]-1,2-thiazin-6-sulphonamide, 3,4-dihydro-2-(3-methoxypropyl)-4-oxo-, 1,1-dioxide 5 (X=Sulphonamide)

The desired compound is prepared according to the general procedure 5 starting from 2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin]-6′-sulphonamide, 1′,1′-dioxide of examples 7 or 8 with a quantitative yield.
¹H-NMR (300 MHz, DMSO-d₆): 8.20 (s, 2H), 7.77 (s, 1H), 4.54 (s, 2H), 3.4-3.1 (m, 7H), 1.78 (m, 2H).
LC-MS: [M+H]⁺=355.

 

///////////PATENT, US 8344136,   PHF S.A., Brinzolamide

Lupin Ltd, Patent, Pitavastatin, WO2014203045

Lupin Ltd, Patent, Pitavastatin, WO2014203045

A NOVEL, GREEN AND COST EFFECTIVE PROCESS FOR SYNTHESIS OF TERT-BUTYL (3R,5S)-6-OXO-3,5-DIHYDROXY-3,5-O-ISOPROPYLIDENE-HEXANOATE

ROY, Bhairabnath; (IN).
SINGH, Girij, Pal; (IN).
LATHI, Piyush, Suresh; (IN).
AGRAWAL, Manoj, Kunjabihari; (IN).
MITRA, Rangan; (IN).
TRIVEDI, Anurag; (IN).
PISE, Vijay, Sadashiv; (IN).
RUPANWAR, Manoj; (IN)

The present invention describes an eco-friendly and cost effective process for the synthesis of teri-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-0-isopropylidene-hexanoate [I]

PITAVASTATIN

TEXT

tert-b tyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-0-isopropylidene-hexanoate [I] [CAS No. 124752-23-4] is key intermediate for the preparation of statins such as Atorvastatin (Tetrahedron 63, 2007, 8124 -8134), Cerivastatin (Journal of Labeled Compounds and Radiopharmaceuticals, 49, 2006 311-319), Fluvastatin [WO2007125547; US 4739073], Pitavastatin [WO2007/132482; US2012/22102 Al, WO2010/77062 A2; WO2012/63254 Al ; EP 304063; Tetrahedron Letters, 1993, 34, 513 – 516; Bulletin of the Chemical Society of Japan, 1995, 68, 364 – 372] and Rosuvastatin [WO2007/125547 A2; WO2011/132172 Al ; EP 521471]. Statins are used for treatment of hypercholesterolemia, which reduces the LDL cholesterol levels by inhibiting activity of HMG-CoA reductase enzyme, which is involved in the synthesis of cholesterol in liver.

[I]

Compound [I] is generally obtained by various methods of oxidation of teri-butyl 2- ((4R,65)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate [compound II] and are discussed in details hereinafter. In addition, various methods for synthesis of compound [II] are also elaborated below.

[II]

[II]

A) tert-butyl2-((4«,6.S)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate

[compound II]

US patent Number 5278313 describes a process for synthesis of compound [II]

(Schemel). In the said process, (5)-methyl 4-chloro-3-hydroxybutanoate has been obtained in only 70% yield through whole cell enzymatic reduction of methyl 4-chloro-3- oxobutanoate, which has a necessity of special equipment such as fermenters as well as other microbial facilities such as sterile area, autoclaves, incubator for growing seed culture, etc.

(S)-mefhyl 4-chloro-3-hydroxybutanoate upon reaction with teri-butyl acetate in presence of LiHMDS or LDA at -78°C, yielded (S)-ieri-butyl 6-chloro-5-hydroxy-3- oxohexanoate, which was further transformed to corresponding diol through syn selective reduction in presence of methoxydiethyl borane/sodium borohydride at -78°C. The diol thus obtained was converted to compound [II] .

The overall yield for this process is low and required special equipment such as fermenters, etc and in addition to that, this process is not cost effective due to use of costly reagent such as methoxydiethyl borane.

Moreover, methoxydiethylborane is highly pyrophoric (Encyclopedia for organic synthesis, editor in chief L. Paquette; 2, 5304; Published by John and Wiley Sons;

Organic Process Research & Development 2006, 10, 1292-1295) and hence safety is a major concern.

Scheme 1

EP 1282719 B l (PCT application WO 01/85975 Al ) discloses a process for synthesis of compound ( R, 5S)-tert-bv y\ 3,5,6-trihydroxyhexanoate from (S)-tert-b tyl-5,6-dihydroxy-3-oxohexanoate through a) asymmetric hydrogenation in presence of a chiral catalyst e.g. di-mu-chlorobis-[(p-cymene)chlororuthenium(II)] along with an auxiliary such as (IS, 2S)-(+)-N- (4-toluenesulfonyl)-l ,2-diphenylethylenediamine as ligand, which gave desired product only in 70% diastereomeric excess (de); b) Whole cell enzymatic reduction of (S)-tert- butyl 5,6-dihydroxy-3-oxohexanoate to obtain compound (3R, 5S)-tert-bv y\ 3,5,6-trihydroxyhexanoate in 99% de (80% yield).

It is needless to mention that it has necessity of fermenter and other microbiological equipment (Scheme 2).

Moreover, conversion of (2>R,5S)-tert-bv y\ 6-acetoxy-3,5-dihydroxyhexanoate to tert-bv yl 2-((4R,65)-6-(acetoxymethyl)-2,2-dimethyl-l ,3-dioxan-4-yl)acetate was accomplished in only 25% yield and also required the flash chromatography for isolation of desired product.

Thus, overall yield for this process is poor and process is not operation friendly especially at large scale hence cannot be considered feasible for commercial manufacturing.

Scheme 2

EP1317440 Bl (PCT Application WO 02/06266 Al) has disclosed the process for synthesis of compound [II] from 6-chloro-2,4,6-trideoxy-D-erythro-hexose (Scheme 3) .

In the said patent application 6-chloro-2,4,6-trideoxy-D-erythro-hexose was converted to (4R, 65)-4-hydroxy-6-chloromethyl-tetrahydropyran-2one with excess of bromine in presence of potassium bicarbonate, which liberates environmentally undesired gas i.e. carbon dioxide.

Moreover, starting material i.e. 6-chloro-2,4,6-trideoxy-D-erythro-hexose is not commercially available and conversion efficiency of starting material at large scale towards (4R, 65)-4-hydroxy-6-chloromethyl-tetrahydropyran-2-one is only 67%.

Scheme 3

US Patent No. 6689591 B2 has demonstrated the whole cell enzymatic reduction of teri-butyl 6-chloro-3,5-dioxohexanoate to compound [II] (Scheme 4).

In the said process, whole cell enzymatic reduction is not specific; yield for desired product is only 34% and other partially reduced products are also obtained.

Hence, further purification is required for obtaining the desired compound. Thus, this process is not suitable for commercial scale.

Scheme 4

Tatsuya et al (Tetrahedron Letters; 34, 1993,513 – 516) has reported synthesis of compound [I] from derivative of L-tartatric acid (Scheme 5).

In the said process, tartaric acid di-i‘sopropyl ester is doubly protected by tert-butyldimethylsilyl group, which was reacted with dianion of teri-butyl acetoacetate to give β, δ-diketo ester compound.

β,δ-diketo ester was reacted with 2 equivalent of diisobutylaluminium hydride (which is a pyrophoric reagent) to afford -hydroxy,8-keto ester in only 60% yield.

This process is not industrially viable as overall yield is very low and also because of use of costly and pyrophoric reagents/chemicals.

Scheme 5

US7205418 (PCT application WO03/053950A1) has described the process for synthesis of compound [II] from (S)-ieri-butyl-3,4-epoxybutanoate (Scheme 6).

The overall yield for this process is very low and moreover, it required the diastereomeric separation of teri-butyl 2-(6-(iodomethyl)-2-oxo-l,3-dioxan-4-yl)acetate by flash chromatography.

Since overall requirement of title compound is very high, any operation involving flash chromatography will tend to render the process commercially unviable.

Scheme 6

Fengali et al (Tetrahedron: Asymmetry 17; 2006; 2907-2913) has reported the process for synthesis of compound [II] from racemic epichlorohydrin (Scheme 7).

In this process, racemic epichlorohydrin was converted to corresponding nitrile intermediate through reaction with sodium cyanide; nitrile intermediate thus obtained was further resolved through lipase catalyzed stereo-selective esterification to obtain (5)-4-(benzyloxy)-3-hydroxybutanenitrile and (R)-l-(benzyloxy)-3-cyanopropan-2-yl acetate;

separation of desired product i.e. (S)-4-(benzyloxy)-3-hydroxybutanenitrile having 98% de (40% yield) was done by column chromatography.

Needless to mention a commodity chemical like compound [I] cannot be manufactured by such a laboratory method, which involved number of steps.

Scheme 7

Bode et al (Organic letters, 2002, 4, 619-621) has reported diastereomer- specific hydrolysis of 1,3-diol-acetonides (Scheme 8).

In this publication, duration of the reaction for diastereomer- specific hydrolysis of 1,3, diol-acetonides is reported to be 4 h, however, in our hand it was observed that hardly any reaction took place in 4 h, which made it non-reproducible.

In addition to that, separation of desired product is achieved by flash chromatography and it is needless to mention that any process which involved flash chromatography would render the process to be commercially unviable.

Hence, additional innovation needs to be put in for making the process industrially viable.

Scheme 8

CN 101613341A has reported the process for synthesis of compound [II] (Scheme

9).

In the same patent application tert-b tyl (S)-6-chloro-5-hydroxy-3-oxohexanoate was synthesized through Blaise condensation of (5)-4-chloro-3-hydorxy-butanenitrile with zinc enolate of tert butyl bromo acetate.

In the literature, synthesis of tert-bv yl (S)-6-chloro-5-hydroxy-3-oxohexanoate was reported through Blaise condensation of silyl protected (5)-4-chloro-3-(trimethylsilyl)oxy-butanenitrile with zinc enolate of tert butyl bromo acetate, in good yield (Synthesis 2004, 16, 2629-2632). Thus, protection of hydroxy group in (5)-4-chloro-3-hydorxy-butanenitrile is imperative.

In the said Chinese patent application, in claim 7, it was mentioned that solvent used for conversion of tert-bv yl (5)-6-chloro-5-hydroxy-3-oxohexanoate to ( R,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate is anyone or mixture of more than one from tetrahydrofuran, ether, methanol, ethanol, n-propanol, /so-propanol and ethylene glycol.

However, in enablement the only example using mixture of solvent was that of THF-methanol (Experimental section, Example 4: The preparation of (R,5)-6-chloro-3,5- dihydroxyhexanoate) and same outcome was expected in other individual or mixture of solvents.

Claim 8 of CN 101613341A mentioned that reduction was carried out by any one or mixture of more than one reducing agents such as sodium borohydride, potassium borohydride, lithium aluminum hydride, diethylmethoxy borane, triethyl borane and tributyl borane.

It implies that either any one of the reducing agents or a mixture of the same can be employed. From reaction mechanism it is very much clear that diethylmethoxy borane, triethyl borane and tributyl borane form the six membered complex between optically active hydroxyl and carbonyl group, which gets reduced by sodium borohydride, signifying that individually diethylmethoxy borane, triethyl borane and tributyl borane are not reducing agents

Moreover, in claims 12 and 13 (Experimental section, Example 4: The preparation of (R,S)-6-chloro-3,5-dihydroxyhexanoate), it is mentioned that reduction should be carried out in temperature range -80 °C to -60 °C, implying that reaction would not work beyond this temperature range i.e. it would work in the temperature window of -80 °C to -60 °C only.

Summarizing, the teachings of the application are not workable.

Scheme 9

Wolberg et al (Angewandte Chemie International Edition, 2000, 4306) has reported that diastereomeric excess for syn selective reduction using mixture of diethyl methoxy borane/sodium borohydride of compound [VI] gave 93% de for compound [VIII], which required further re-crystallization to obtain compound [VIII] in 99% de and 70% yield.

Thus, all the reported methods for stereo-selective hydride reduction of compound [VI] were achieved through mixture of trialkyl borane or diethyl methoxy borane & sodium borohydride in THF, at -78°C. As mentioned earlier, trialkyl borane or diethyl methoxy borane are pyrophoric in nature; in addition to that anhydrous THF is costly and moreover, reaction required large dilution.

Hence, there is need for developing efficient, environment friendly, cost effective and green process for stereo-selective reduction compound [VI].

B) The process of Oxidation of compound [II] to compound [I] has been discussed in following literature processes.

1) Swern oxidation (US4970313; Tetrahedron Letters, 1990, 2545

Synthetic Communications, 2003, 2275 – 2284).

2) Parrkh-Doering oxidation (J. Am. Chem. Soc, 1967, 89, 5505-5507)

3) TEMPO/NaOCl oxidization (EP2351762)

4) Trichloroisocyanuric acid/ TEMPO (CN 101747313A)

5) Oxidation of compound [II] to compound [I] through IBX [CN101475558A].

It would be evident that most of the reported methods are not “green” and

environmentally benign; none of the reported methods use molecular oxygen as oxidizing agent in presence of metal catalyst/co-catalyst.

Example 18: Process for synthesis of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate [I]

A reactor was charged with 1.1 g of copper (I) chloride and 10 mL of acetonitrile. 2-2′ Bipyridyl (156 mg) and TEMPO (156 mg) were added to the reactor under oxygen environment at 25°C. A solution of (6-Hydroxymethyl-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester 2.6 g in 26 mL DCM was added dropwise over a period of 10 min into it. The reaction mass was stirred at 40°C and progress of reaction was monitored on GLC, which shows that 90% conversion for desired product.

Example 19: Process for synthesis of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate [I]

A reactor was charged with 1.1 g of copper (I) chloride and 10 mL of dichlorome thane. 2-2′ Bipyridyl (156 mg) and TEMPO (156 mg) were added to the reactor under oxygen environment at 25°C. A solution of (6-Hydroxymethyl-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester 2.6 g in 26 mL DCM was added dropwise over a period of 10 min into it. The reaction mass was stirred at 40°C and progress of reaction was monitored on GLC, which shows that 90% conversion for desired product.

SEE………https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014203045&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCT+Biblio

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