WO2012032531A1

WO2012032531A1 - Process for the manufacture of irinotecan hydrochloride by total synthesis

Info

Publication number: WO2012032531A1
Application number: PCT/IN2010/000754
Authority: WO
Inventors: Venkata Rama Rao Alla; Ramakrishna Rao; Chandrashekar Ramarao; Ramadevi Nandipati; Vinay Avinash Chamle
Original assignee: Avra Laboratories Pvt. Ltd.
Priority date: 2010-09-06
Filing date: 2010-11-19
Publication date: 2012-03-15

Abstract

Disclosed herein is a highly safe and easily scalable process for the production of 7-Ethyl- 10-hydroxycamptothecin and its conversion to Irinotecan hydrochloride by total synthesis.

Description

PROCESS FOR THE MANUFACTURE OF IRINOTECAN HYDROCHLORIDE

BY TOTAL SYNTHESIS

Field of Invention:

This invention relates to a process for the manufacturing of 7-Ethyl-10- hydroxycamptothecin (SN-38), by condensing two synthetic intermediates namely 2- Amino-5-hydroxy propiophenone and 5'-(S)- l ,5-Dioxo-(5'-ethyl-5'-hydroxy- 2'H,5h,6'H-6-oxopyrano)-[3',4'f]-A⁶⁽⁸⁾-tetrahydroindolizine (referred as (S)-Trione). SN-38 is then converted to Irinotecan hydrochloride of high purity.

Background of the invention:

Irinotecan hydrochloride, (S)-4, l l-diethyl-3,4, 12,14-tetrahydro-4-hydroxy-3,14-dioxo- lH-pyrano[3 4 6 7]-indolizino[l,2-b]quinolin-9yl[l,4'-bipiperidino]-r-carboxylate hydrochloride,

having formula (1) is a camptothecin analog and a topoisomerase I inhibitor derived from camptothecin, a natural product extracted from a Chinese tree, camptotheca acumineta.

Figure 1 :

Irinotecan hydrochloride has been approved in the United States in 1996 for the treatment of colorectal and other gastrointestinal cancers, small cell and non-small cell lung cancer and other malignancies.

Sawada et.al., Chem. Pharma. Bull. 1991, 1446-1454, described the preparation of irinotecan hydrochloride trihydrate (1 ) from natural camptothecin in five steps (Figure 1 ) and in about 20% yield. The semi-synthetic approach for the preparation of camptothecin and its derivatives has been reported in US Patent nos. 4,604,463, 4,545,880 and 4,473,692, European Patent EP0074256, as well as Japanese Patent nos. JP84/46,284 and JP84/51,287

Figure 1 :

CAMPTOTHECIN 7-ETHYL CAMPTOTHECIN HLORIDE

SN-38

7-ETHYL-10-HYDROXYCAMPTOTHECIN

Natural camptothecin contains related impurities and are difficult to remove resulting final irinotecan hydrochloride carries these impurities and the use of chromatographic purification at the final compound (1) is desirable, eg. US 4,473,692. Further the availability of natural camptothecin may also limit the availability of irinotecan and other synthetic analogs.

Camptothecin synthesis was first reported by Wani et.al. [J. Med. Chem. 1980, 554] by adopting Friedlander synthesis and the same was extended by Tagawa et.al. (U S Patent no. 1988, 4,778,891) for the synthesis of SN-38 which is then converted to Irinotecan. SN-38 is made by condensing 2-Amino-5-hydroxypropiophenone (3) with S-Trione (4) in accordance with the following scheme (Figure 2). Earlier we have reported a simple and convenient method of manufacturing 2-Amino-5-hydroxypropiophenone (3) which was disclosed in PCT/TN2005/000326, WO2007/015259 corresponding to U S Patent US2008221358 Al and the preparation of (S)-Trione (4) by an improved method (Patent filed) based on literature report by Wani.et.al. (J. Med. Chem. 1980, 554; 1986, 1553)

(USP 2000, 6,121,451 see also J.Org.Chem.1997, 6588)

Henegar et.al was the first to report the total synthesis of 7-Ethyl- 10- hydroxycamptothecin (SN-38) by reacting (S)-Trione (4) and AHPP (3) at 95 - 100°C in a mixture of toluene and acetic acid in presence of PTS acid for about 18 to 24 hrs. Toluene and acetic acid are removed by distillation to yield SN-38 (2) which is converted to Irinotecan hydrochloride without purification. The compound (2) is dissolved in pyridine and reacted at 20 - 25°C with l-Chlorocarbamoyl-4-piperidinopiperidine, dissolved in CH₂C1₂. The solvents are removed by distillation and the free base is then chromatographed on silica gel eluting with a mixture of CH₂C1₂ and methanol and finally crystallized, washed with ethanol and dried to yield 62% of Irinotecan Hydrochloride. The purity of Irinotecan is not given.

In another method (WO 2006/082279 A l , (S)-Trione and AHPP are taken in a mixture of toluene and acetic acid in presence of PTS acid and heated rapidly to 100°C. The emphasis is on to raise the temperature to 100°C within 10 to 30 minutes and left at that temperature for 5 to 8 hrs. The solvent was removed and a suitable crystallization solvent such as n-butanol is added, heated to dissolve and cooled to effect crystallization. The product (SN-38) thus obtained with 90% yield and 99.8% purity by HPLC. This compound is then converted to irinotecan by condensing with l-Chlorocarbamoyl-4- piperidinopiperidine in pyridine and CH₂C1₂ as medium using Et₃N as base. Other reports for the preparation of 7-Ethyl-lO-hydroxycamptothecin and its conversion to Irinotecan are also described in general terms. All of them use pyridine as the medium with or > without other solvents and also as a base in the preparation of irinotecan. '

As the demand for irinotecan hydrochloride is growing and the non availability of pure natural camptothecin is the limiting factor, it is appropriate to look into the total synthesis that can be exploited for commercial reasons including to attain high purity. We embarked on for the first time the total synthesis of AHPP (3) and (S)-Trione (4) and their conversion to 7-Ethyl-10-hydroxycamptothecin (SN-38; 2) by a simple Friedlander condensation in presence of strong acid. The SN-38 thus obtained is 99.8% pure and is converted to irinotecan hydrochloride avoiding pyridine as the medium resulting in the formulation of final compound in high yield with high purity.

Summary of the invention:

In accordance with the above object, the present invention provides a process for preparation of 7-Ethyl-10-hydroxycamptothecin (2) with a purity >99% comprising:

a) reacting AHPP (3) and (S)-Trione (4) in a solvent medium using a catalyst at a temperature ranging 80-90°C to obtain 7-Ethyl- 10-hydroxycamptothecin and

b) purifying 7-Ethyl-10-hydroxycamptothecin in acetic acid containing 2 to 5% H₂0.

The preferable catalyst according to the invention is triflouroacetic acid and the solvent is selected from a hydrocarbon or acetic acid. The hydrocarbon solvent is selected from benzene, toluene and hexane. One preferred hydrocarbon solvent is toluene.

According to one aspect, the preparation of 7-Ethyl-10-hydroxycamptothecin is carried out in toluene as solvent, wherein trifluroacetic acid is used in 1 .0 eq. wt/wt with reference to (S)-Trione. After completion of the reaction, the toluene layer is removed and diluted the viscous acid layer with isopropyl alcohol to obtain 7-Ethyl-10- hydroxycamptothecin .

According to another aspect, the preparation of 7-Ethyl-lO-hydroxycamptothecin is carried out in acetic acid as solvent medium, wherein trifluro acetic acid is used in an amount of 2 to 10% with reference to acetic acid.

According to the process of present invention, the solvent is either toluene or acetic acid used in an amount of 4 to 20 volumes with reference to (S)-Trione compound.

In yet another aspect, 7-Ethyl-10-hydroxy camptothecin thus obtained is converted into irinotecan hydrochloride by reacting with l-Chlorocarbamoyl-4-piperidinopiperidine in CH₂CI₂ using N-methylpyrrolidine as a base followed by treatment with hydrochloric acid. The irinotecan hydrochloride thus obtained is purified from a mixture of IPA -water. The mixture of IPA and water for the purification of irinotecan hydrochloride may be used in a ratio of 1 : 1 to 1 :4.

Irinotecan hydrochloride prepared according to the present invention having a purity of more than 99.7% by HPLC.

In another aspect, l -Chlorocarbamoyl-4-piperidinopiperidine is prepared by reacting 4- piperidinopiperidine with triphosgene in CH₂C1₂ medium and washing the resultant compound with ethyl acetate or any other organic inert solvent(s) to obtain the product with a purity of upto 95%..

Detailed description of the invention:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. The phrase 'SN-38' and '7-Ethyl-lO-hydroxycamptothecin' is used interchangeably throughout the specification and and the same may be appreciated as such by the person skilled in the art.

Accordingly, the present inventors conducted extensive investigations at every stage and finally arrived at a commercially feasible route for the synthesis of AHPP (3) and (S)- Trione (4). It is then further directed to a preparation of 7-Ethyl-lO-hydroxycamptothecin (SN-38; 2) and its conversion to irinotecan hydrochloride (1 ) by a simple, scalable method giving high yield and high purity at each stage.

The main aspect of this invention is to condense AHPP and (S)-Trione in presence of strong organic acid in a suitable solvent, which can be aromatic or aliphatic hydrocarbon. The ratio of organic acid and the solvent is not critical but both are required to achieve smooth transformation. The organic acid, that the present inventors found to be suitable is trifluoroacetic acid. The quantity of organic acid taken is equal to the quantity of (S)- Trione, used together with approximately 10 times hydrocarbon solvent to conduct the reaction. One preferable hydrocarbon solvent is toluene, which is the most appropriate to carry out this reaction. The reaction is best carried out by heating the reaction mass containing a mixture of AHPP and (S)Trione in the above medium for 15 to 20 hrs at 80- 90°C, cooling the medium, removing the upper toluene layer, adding isopropyl alcohol (10 to 15 times of the wt. of the trione) to yield SN-38 in 95% yield. SN-38 thus obtained can be recrystalized with dilute acetic acid (2 to 5% H₂0 in acetic acid) to give colourless crystalline compound with purity of >99.7% by HPLC.

In an another process variant, SN-38 can also be prepared by heating a mixture of AHPP and (S)-Trione in acetic acid containing 2 to 10% trifluoroacetic acid and the resulting product is then crystallized in dilute acetic acid as indicated above. By this approach also, SN-38 is obtained with a purity of >99.7% and the overall yield is -90%.

According to the process of present invention, 7-Ethyl-lO-hydroxycamptothecin has been made in kilo quantities in several batches retaining the same purity and yield making the process easily scalable to industrial level. 7-Ethyl-lO-hydroxycamptothecin (SN-38) is then converted to irinotecan hydrochloride by reacting with l -Chlorocarbamoyl-4- piperidinopiperidine hydrochloride using a base and CH₂C1₂ as the medium. All the previous methods of synthesis of irinotecan from SN-38 invariably used pyridine as base / solvent with or without other organic solvents such as CH2CI2 and bases such as Et₃N, N- Ethyldiisopropylamine, 4-dimethylaminopyridine etc. If the starting SN-38 is derived from natural camptothecin, then it is essential to purify irinotecan base by column chromatography over silica gel. Alternately, if irinotecan is synthesized, the removal of pyridine below 45°C is essential to obtain good quality of irinotecan. The present inventors felt that the use of pyridine in the process is not advisable, due to various hazardous and environmental issues associated with its use and hence looked for a method avoiding pyridine altogether in the process of preparing irinotecan.

Now the inventors have found out that N-methylpyrrolidine is the most suitable base replacing altogether pyridine in the manufacture of irinotecan hydrochloride. Accordingly, SN-38 is suspended in CH₂C1₂ (20 times the wt.) and reacted with 1 - chlorocarbamoyl-4- piperidinopiperidine hydrochloride (2 eq.) in presence of . N- Methylpyrrolidine (7 eq.) at room temperature followed by purification and salt formation to give irinotecan hydrochloride in 80% overall yield with purity >99.7% with no impurity greater than 0.1%. The optical purity of the (S)-Isomer is 99.8% (R-lsomer less than 0.1%).

In yet another embodiment, the irinotecan hydrochloride is further purified by taking in isopropyl alcohol -water mixture (1 :3), heated to 70°C and adjusted the pH to 3.5 to 3.8 by adding 5% hydrochloride to form clear solution. The solution is then allowed to cool to room temperature, collected the product by filtration, washed with IPA-H₂0 (1 :3) and dried at room temperature to give colourless crystalline compound of irinotecan hydrochloride of 99.78% purity by HPLC with no impurity >0.1%. However, the IPA- water mixture may also be used in the ratio of 1 : 1 , 1 : 2 or 1 :4 to achieve the similar effect. In yet another embodiment, l-Chlorocarbamoyl-4-piperidinopiperidine is prepared by reacting 4-piperidinopiperidine with triphosgene in CH₂CI₂ medium and washing the resultant compound with ethyl acetate or any other organic inert solvent(s).

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.

Examples:

Example 1 : 7-Ethyl-lO-hydroxycamptothecin (2)

2-Amino-5-hydroxypropiophenone (AHPP; 2.08 kg) and (S)-Trione (2.70kg) along with trifluoroacetic acid (2.7 L) were taken in toluene (13.5 L) in a 25 L reactor. The contents were heated to 85-90°C for 15 to 20 hrs (in process check shows the absence of (S)- Trione by HPLC). The contents were allowed to cool to room temperature and the upper toluene layer was removed and rejected. To the viscous bottom acidic layer, isopropyl alcohol (40.0 L) was added and the contents were heated to reflux (80-90°C) for. 30 minutes and allowed to cool to room temperature. The solid was collected, washed with acetone (20 L) and air dried. Yield 3.9 kg (95%).

The above compound was recrystalized by taking into dilute acetic acid (2.5% water in acetic acid; 40 L), heating to 100°C for 1 hour, cooled to room temperature with stirring. The colourless crystalline product was filtered and washed with isopropyl alcohol (14 L) followed by acetone (20 L) and dried at 40°C under vacuum. The yield was 3.20 kg (82%), HPLC purity 99.8% [a]_D = -32C.

Example 2: 7-Ethyl-10-hydroxycamptothecin

(S)-Trione (500 g), AHPP (350 g), Trifluoroacetic acid (100 ml) and acetic acid (2.4 L) were heated to 85-90°C for 20 hrs. The reaction mixture was cooled and the solid was collected by filtration (650 g) purity 99.1% by HPLC. The compound was further purified by dissolving in acetic acid mixed with 2.5 % water (6.5 L) and heated to boil. The solution was allowed to cool to room temperature and the product was collected, washed with acetone and dried under reduced pressure keeping the temperature below 50°C for 5 hrs. The colourless solid (560.0 g) analyzed 99.7% pure by HPLC and no single impurity was present >0.1 %.

Example 3: l-Chlorocarbamoyl-4-piperidinopiperidine hydrochloride

Triphosgene (120 g; 0.68 eq.) is taken in dichloromethylene (1 L) and to this cold solution (keeping the temperature between 0-5 °C) 4-Piperidinopiperidine (100 g) in CH₂C1₂ (1 L) was added slowly for 4 hrs. The solution was then allowed to cool to room temperature and stirred for further 12 hours. The solvent was removed, ethyl acetate (1 L) was added, stirred and collected the compound by filtration. The white solid was then dried at room temperature under reduced pressure. The product thus obtained is 94-95% pure and contains mostly bis-urea derived from 4-piperidinopiperidine with an yield of 140 g (88.6%). The product was used as such in the next step of making irinotecan hydrochloride.

Example 4: Irinotecan hydrochloride

7-Ethyl-lO-hydroxycamptothecin (20 g) was suspended in methylene chloride (400 ml). To this while stirring at room temperature l-chlorocarbonyl-4-piperidinopiperidine hydrochloride (27.2 g; 2 eq.) and N-methylpyrrolidine (40.0 ml; 7 eq.) was added. There was visible temperature raise of 5°C in the next 10 to 20 minutes and stirred for further 30 minutes to dissolve, all the suspended material into solution. The clear solution was further stirred for additional 2 hours (In process check shows the absence of SN-38). The solvent was removed along with excess of N-Methylpyrrolidine under reduced pressure, keeping the temperature below 45°C. After cooling the solid mass was treated with water (250 ml) and stirred. To this aqueous solution, methylene chloride (1 L) was added and stirred well to extract all the free base of irinotecan. The organic layer was collected, washed with water twice (250 ml x 2), solvent was removed to give pale yellowish solid The free base is suspended in 280 ml of water and to this 16.3 ml of concentrated hydrochloride (3 eq.) was added and stirred at room temperature for 15 minutes to form clear solution. The solution was then heated to 70°C for 3 hrs and slowly allowed to cool to room temperature. It was further cooled to 0-5°C for 30 minutes, collected the solid, washed with water (60 ml), ethanol (60 ml) and dried at room temperature to give 30 g of irinotecan hydrochloride, purity 99.5% (yield 90%).

The above compound is further purified by taking in isopropyl alcohol -water mixture (24 ml); (6 ml isopropyl alcohol and 18 ml of H₂0) and heated to 70°C and adjusted the pH to 3.5 to 3.8 by adding 5% hydrochloride (0.2 ml) to form clear solution. The solution was then allowed to cool to room temperature, collected the product by filtration, washed with IPA-H₂0 (1 :3) and dried at room temperature to give 2.6 g of colourless crystalline compound of irinotecan hydrochloride of 99.78% purity by HPLC with no impurity >0.1%.

Claims

We claim,

1. A process for preparation of 7-Ethyl-lO-hydroxycamptothecin (2) with a purity >99% comprising:

a) reacting AHPP (3) and (S)-Trione (4) in a solvent medium using a catalyst at a temperature ranging 80-90 °C to obtain 7-Ethyl-10- hydroxycamptothecin; and

b) purifying 7-Ethyl- lO-hydroxycamptothecin in acetic acid containing 2 to 5% H₂0.

2. The process according to claim 1, wherein said catalyst is triflouroacetic acid.

3. The process according to claim 1, wherein the solvent is selected from a hydrocarbon or acetic acid.

4. The process according to claim 3, wherein the hydrocarbon solvent is selected from benzene, toluene, hexane.

5. The process according to claim 4, wherein the solvent is toluene.

6. The process according to claim 5, wherein the catalyst is used in 1.0 eq. wt/wt with reference to (S)-Trione.

7. The process according to claim 5, further comprising a step of removing toluene followed by diluting acid layer with isopropyl alcohol to obtain 7-Ethyl-10- hydroxycamptothecin .

8. The process according to claim 3, wherein the solvent is acetic acid.

9. The process according to claim 1, wherein the solvent is either toluene or acetic acid used in an amount of 4 to 20 volumes with reference to (S)-Trione compound.

10. The process according to claim 8, wherein trifluro acetic acid is used in an amount of 2 to 10% when reference to acetic acid.

11. The process according to any one of preceding claim, wherein said process further comprising a step of converting 7-Ethyl-10-hydroxy camptothecin into irinotecan hydrochloride by reacting with l-Chlorocarbamoyl-4-piperidinopiperidine in CH₂C1₂ using a base followed by treatment with hydrochloric acid and purifying the irinotecan hydrochloride from a mixture of IPA-water.

12. The process according to. claim 1 1 , wherein said base is N-methylpyrrolidine.

13. The process according to claim 11, wherein the IPA and water is used in a ratio of 1 : 1 to 1 :4.

14. A process for preparation of irinotecan hydrochloride comprising:

a) reacting 7-Ethyl-10-hydroxy camptothecin with l-Chlorocarbamoyl-4 piperidinopiperidine in CH2CI2 using a base;

b) converting irinotecan into irinotecan hydrochloride by treating with hydrochloric acid; and

c) purifying irinotecan hydrochloride from I PA -water mixture.

15. The process for preparation of irinotecan hydrochloride according to claim 14, wherein said base is N-methylpyrrolidine.

16. The process for preparation of irinotecan hydrochloride according to claim 14, wherein the IPA and water is used in a ratio of 1 : 1 to 1 :4.

17. Irinotecan hydrochloride prepared according to claims 11 or 14, having a purity of more than 99.7% by HPLC.

18. The process according to claims 1 1 or 14, wherein the l -Chlorocarbamo^'yl-4- piperidinopiperidine is prepared by reacting 4-piperidinopiperidine with triphosgene in CH₂C1₂ medium and washing the resultant compound with ethyl acetate or any other organic inert solvent(s).