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WO2007069268A2 - A process for the preparation of substantially pure 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives - Google Patents

A process for the preparation of substantially pure 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives Download PDF

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Publication number
WO2007069268A2
WO2007069268A2 PCT/IN2006/000414 IN2006000414W WO2007069268A2 WO 2007069268 A2 WO2007069268 A2 WO 2007069268A2 IN 2006000414 W IN2006000414 W IN 2006000414W WO 2007069268 A2 WO2007069268 A2 WO 2007069268A2
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Prior art keywords
formula
compound
pharmaceutically acceptable
substantially pure
carboxylic acid
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PCT/IN2006/000414
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French (fr)
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WO2007069268A3 (en
Inventor
Rajesh Lalmani Giri
Sudhakar Kambhampati
Trinadha Rao Chitturi
Rajamannar Thennati
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Sun Pharmaceutical Industries Limited
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Publication of WO2007069268A3 publication Critical patent/WO2007069268A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to a process for the preparation of substantially pure l ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives, compound of formula I and pharmaceutically acceptable salt thereof, wherein Et represents ethyl group; and X and Y are independently selected from the group consisting of hydrogen, (C
  • Et represents ethyl group
  • X and Y are independently selected from the group consisting of hydrogen, (C
  • the compound of formula I is useful in therapy for the treatment of hypertension.
  • the present invention relates to a process for the preparation of compound of formula Ia, wherein X and Y, both are H, commonly known as quinapril and compound of formula Ib, wherein X and Y both are OCH 3 , commonly known as moexipril.
  • United States Patent No. 4,344,949 discloses compound of formula I and process for preparation thereof from its esters, namely lower alkyl esters, arylmethyl ester or trimethylsilyl ester.
  • United States Patent No. 6,617,457 discloses process for preparation of compound of formula Ia by hydrogenolysis of compound of formula II (X and Y are both H) with Pd/C in an alcoholic solvent in the presence of concentrated hydrochloric acid.
  • the catalyst is filtered off, solvent is removed by distillation followed by repeated addition of toluene and removal of solvent by vacuum distillation.
  • the quinapril hydrochloride is isolated in the form of a toluene solvate.
  • the toluene solvate is treated with a class 3 solvent to get the corresponding solvate which is then dried to obtain quinapril hydrochloride.
  • PCT publication Number WO 2004/054980 discloses process for preparation of compound of formula Ia by hydrogenolysis of compound of formula II (X and Y are both H) with Pd/C in an alcoholic solvent in the presence of 35% hydrochloric acid. After completion of reaction the catalyst is filtered off and the filtrate is evaporated to give crude quinapril hydrochloride. It is then subjected to further purification by repeated extractions with dichloromethane and concentration followed by formation of a nitroalkane solvate and drying to give quinapril hydrochloride, reportedly in 65 % yield only.
  • GB 2095252A discloses catalytic hydrogenolysis of compound of formula II (X and Y are both H) with hydrogen and Pd/C in elhanol. After completion of reaction the catalyst is filtered, the solvent concentrated in vacuo, and the product partitioned between ether and 2N HCl followed by lyophilization.
  • This process has the disadvantage that the compound of formula I formed in this reaction as free base is unstable and partially converts to the diketopiperazine impurity, a compound of formula A. This results in quinapril in yield of only 37 %. Further, lyophilization on industrial scale being energy intensive renders the process economically unviable.
  • the impurities diketopiperazine, compound of formula A, the diacid, compound of formula B and ethyl diester, compound of formula C may be formed due to various reaction conditions used in the synthesis and isolation process.
  • the compound of formula I is a sensitive molecule and is unstable in its free base form.
  • the side chain nitrogen is unprotonated it undergoes facile intramolecular cyclization to give diketopiperazine impurity, compound of formula A. Therefore the arylmethyl ester, compound of formula II is first protonated by converting into hydrochloride with concentrated HCl and then subjected to hydrogeno lysis in an alcoholic solvent in some of the prior art processes described vide-si ⁇ ra.
  • the hydrochloride salt of compound of formula I is soluble in water as well as in alcohol, the process of isolation of the compound of formula I in prior art processes involves removal of these solvents from the reaction mixture by the process of distillation.
  • substantially pure compound of formula I or pharmaceutically acceptable salts thereof means a compound of formula I or pharmaceutically acceptable salts thereof, which has impurity A in less than 0,5%, impurity B in less than 0.5% and impurity C in non-detectable amounts; preferably impurity A is less than 0.2%, impurity B is less than 0.2% and 0% impurity C, as measured by HPLC (high performance liquid chromatography) analysis.
  • the present invention provides a safe and convenient process for the preparation of compound of formula I or a salt thereof by hydrogenolysis of compound of formula II or acid addition salt thereof in an aqueous medium, in presence of acid.
  • the catalyst is filtered off and product is extracted from the reaction mixture with water immiscible organic solvent, thereby avoiding removal of hydrogenolysis solvent system by heating.
  • the process avoids conditions that are detrimental to the product quality, i.e. heating of the reaction mixture with a potentially pro-impurity forming composition of acid, alcohol and water.
  • the end result is minimization of the formation of impurities, especially compounds of formulae A & B, and prevention of impurity C, to obtain substantially pure compound of formula I or a salt thereof.
  • the present invention in one aspect provides a process for preparation of substantially pure l,2,3,4-tetrahydiOisoquinoline-3-carboxylic acid, compound of formula I or its pharmaceutically acceptable salt comprising: a) subjecting compound of formula II or acid addition salt thereof to hydrogenolysis in aqueous medium in the presence of an acid;
  • Et represents ethyl group
  • Ar represents phenyl or substituted phenyl group
  • the present invention in one aspect provides a process for industrial scale preparation of substantially pure l,2,3,4-tetral ⁇ ydroisoquinoline-3-carboxylic acid, compound of formula I or pharmaceutically acceptable salt thereof comprising: a) subjecting compound of formula II or acid addition salt thereof to hydrogenolysis in aqueous medium in the presence of an acid;
  • Formula I Formula II wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl group; and X and Y are independently selected from the group consisting of hydrogen, (Ci-C 3 )-alkyl or O-(Ci-C 3 )-alkyl or X and Y can be linked together to form a cyclic group -0(CH 2 )Ii-O-, wherein n lor 2. b) extracting the product from the reaction mixture with water immiscible organic solvent and c) isolating the compound of formula I or its solvate as a pharmaceutically acceptable salt thereof.
  • the present invention provides a safe and convenient process for the preparation of substantially pure 1,2,3,4— tefrahydroisoquinoline-3-carboxylic acid, compound of formula I or pharmaceutically acceptable salt thereof from compound of formula II or acid addition salt thereof.
  • Formula I ' Formula II wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl group wherein phenyl ring is substituted with one or more halogen, O-(CpC 4 )-alkyl or haloalkoxy group containing Ci-C 4 alkyl, for example, -OCF 3 group and the like and X and Y are independently selected from the group consisting of hydrogen, (Ci-C 3 )-alkyl or O-(C-i-C 3 )-alkyl or X and Y can be linked together to form a cyclic group — 0(CH 2 )n-0-, wherein n l or 2.
  • the present invention provides a process for preparation of substantially pure l,2,3,4-tetraliydroisoquinoline-3-carboxylic acid, compound of formula I or its pharmaceutically acceptable salt comprising: a) subjecting compound of formula II or acid addition salt thereof to hydrogenolysis in aqueous medium in the presence of an acid;
  • Et represents ethyl group
  • Ar represents phenyl or substituted phenyl group
  • the compound of formula I or its solvate is isolated as a pharmaceutically acceptable salt thereof by removing the solvent from said organic extract by any method known in the art like removal of solvent by heating.
  • the present invention provides a process for industrial scale preparation of substantially pure l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid compound of formula I or pharmaceutically acceptable salt thereof comprising a) subjecting compound of formula II or acid addition salt thereof to hydrogenolysis in aqueous medium in the presence of an acid;
  • the batch size for industrial scale is preferably at least about 0.5 kg.
  • Example 1 illustrates such an industrial process, which prepares the compound of formula I in a batch having about 10 kg.
  • the present invention provides a process for the preparation of substantially pure ,l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, compound of formula I or pharmaceutically acceptable salt thereof, wherein X and Y both are H.
  • the present invention provides a process for the preparation of substantially pure l,2,3,4-tetrahydrojsoquinoline-3-carboxylic acid, compound of formula I or pharmaceutically acceptable salt thereof, wherein X and Y both are OCH 3 .
  • the aqueous medium for hydrogenolysis maybe selected from water or a mixture thereof with a solvent selected from ketones such as acetone, methyl ethyl ketone and the like; amides such as dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, ureas and the like, nitriles such as acetonitrile and the like.
  • a solvent selected from ketones such as acetone, methyl ethyl ketone and the like; amides such as dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, ureas and the like, nitriles such as acetonitrile and the like.
  • the hydrogenolysis medium is water and acetone mixture. Any suitable volume ratio of water and acetone may be used depending on the amount of the compound of formula II to be subjected to hydrogenolysis.
  • a suitable quantity and composition of water and acetone solvent mixture to be used for hydrogenolysis may be determined by one skilled in the art. The quantity and composition is chosen such that the compound of formula II that is to be subjected to hydrogenolysis dissolves to form a homogeneous solution at the temperature at which the hydrogenolysis reaction is carried out.
  • the present invention provides a process for preparation of substantially pure 1,2,3,4— tetrahydroisoquinoline-3-carboxylic acid, compound of formula I or pharmaceutically acceptable salt thereof, wherein X and Y both are H, comprising subjecting a compound of formula II or acid addition salt thereof, wherein X and Y both are H, to hydrogenolysis in aqueous medium in the presence of an acid, wherein the aqueous medium comprises of water and acetone mixture in the volume ratio of 1: 1.
  • the hydrogenolysis of compound of formula II in aqueous medium may preferably be carried out in presence of concentrated HCl or solution of hydrogen chloride in a suitable solvent.
  • the hydrogenolysis in aqueous medium may be carried out using any suitable hydrogen source, for example, hydrogen gas at a pressure between 0-20 bar and at a temperature between -20 to 50°C in the presence of any suitable hydrogenation catalyst, for example, 10% palladium on charcoal.
  • any suitable hydrogen source for example, hydrogen gas at a pressure between 0-20 bar and at a temperature between -20 to 50°C in the presence of any suitable hydrogenation catalyst, for example, 10% palladium on charcoal.
  • Any suitable water immiscible organic solvent can be used for the extraction of compound of formula I obtained by hydrogenolysis of compound of formula II.
  • a non-protic and volatile organic solvent for example, aliphatic halogenated hydrocarbons such as dichloromethane, ethylene dichloride or chloroform may be used.
  • the pharmaceutically acceptable salt of compound of formula I may be selected from hydrochloride, hydrobromide, sulfate, nitrate, acetate, fumarate, maleate, citrate and the like.
  • the acid addition salts of compounds of formula II may be selected from hydrochloride, maleate, hydrobromide, sulfate, nitrate, acetate, fumarate, maleate, citrate and the like.
  • the present invention provides substantially pure 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, compound of formula I which is substantially free of impurities represented by formulae A, B and C and solvates and salt thereof.
  • the present invention provides substantially pure 1,2,3,4— tetrahydroisoquinoline-3-carboxylic acid, compound of formula I which contains a compound of formula A in less than 0.5%, a compound of formula B in less than 0.5% and compound of formula C is in non-detectable amount as measured by HPLC analysis.
  • the present invention provides substantially pure 1,2,3,4- tetrahydiOisoquinoline-3-carboxylic acid, compound of formula I which contains a compound of formula A in less than 0.5%, a compound of formula B in less than 0.5% and compound of formula C is 0% as measured by HPLC analysis.
  • the present invention provides substantially pure 1 ,2,3,4— tetrahydroisoqumoline-3-carboxylic acid, compound of formula I which contains a compound of formula A in less than 0.2%, a compound of formula B in less than 0.2% and compound of formula C is in non-detectable amount as measured by HPLC analysis.
  • the present invention provides substantially pure 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, compound of formula I which contains a compound of formula A in less than 0.2%, a compound of formula B in less than 0.2% and compound of formula C is 0% as measured by HPLC analysis.
  • the catalyst is removed by filtration.
  • the reaction mixture is then extracted with a water immiscible organic solvent.
  • the compound of formula I or its solvate or a pharmaceutically acceptable salt thereof may be isolated by removing the organic solvent from the extract, preferably under vacuum at the temperature preferably below 5O 0 C.
  • the isolated compound of formula I or a pharmaceutically acceptable salt thereof can be dissolved in another organic solvent and crystallized out as a solvate thereof, for example, acetone solvate or acetonitrile solvate, optionally by seeding if required, which may then be converted to a compound of formula I or a pharmaceutically acceptable salt thereof by drying the product, preferably under vacuum at a temperature preferably below 50 0 C.
  • the step of formation of solvate of compound of formula 1 may be repeated if desired.
  • a compound of formula Ia, quinapril or a pharmaceutically acceptable s.alt is prepared by subjecting the compound of formula II (wherein X and Y are both H) to hydrogenolysis in an aqueous medium containing acetone in the presence of a hydrogenation catalyst like palladium on carbon (Pd/C), hydrogen source like hydrogen gas and hydrochloric acid at a temperature of about 4O 0 C.
  • a hydrogenation catalyst like palladium on carbon (Pd/C)
  • hydrogen source like hydrogen gas
  • hydrochloric acid at a temperature of about 4O 0 C.
  • the catalyst is removed by filtration and the aqueous reaction mixture is extracted with a water immiscible organic solvent like dichloromethane.
  • the organic solvent is removed by heating under vacuum, preferably at / below 40°C.
  • the residue is dissolved in acetone and the product is crystallized out, preferably by cooling to about 0 to about 10 0 C, filtered and dried under vacuum, preferably below a temperature of 5O 0 C to obtain quinapril or a pharmaceutically acceptable salt thereof.
  • the process of the present invention provides substantially pure 1,2,3,4— tetrahydroisoquinoline-3-carboxylic acid derivatives, compound of formula I, with purity greater than 98%, as determined by HPLC.
  • the compound of formula II may be prepared by a method known to those skilled in the art such as United States Patent No. 4,344949, which is incorporated herein by reference.
  • the maleate salt of compound of formula II, 10 kg (wherein Ar represents phenyl, Et represents ethyl group; and X and Y are both hydrogen) was suspended in DM water, and its free base was extracted into dichloromethane after adjusting pH to 8.0 to 8.5 with 10% sodium carbonate solution.
  • the dichloromethane extract was concentrated under reduced pressure and degassed under vacuum. The residue was taken up in a mixture of 20 litres of DM water and 20 litres of acetone and 1.0 kg 5%Pd/C (50% wet) and 4 litres of 35% hydrochloric acid were added.
  • the reaction mass was subjected to catalytic hydrogenolysis with hydrogen gas for 5.0 hours at 35-4O 0 C at 0.5 kg/sq.cm pressure, and the catalyst was filtered.
  • the filtrate was extracted with dichloromethane, the extract concentrated at below 35 0 C under reduced pressure, and resulting residue was stripped with acetone under vacuum. The residue thus obtained was stirred with acetone, and cooled to 5-1O 0 C.
  • the liquid chromatograph is equipped with a 214 nm UV detector and 25cm x 4.0mm, 5 ⁇ column that contains Superspher ® RP 8. The flow rate is maintained at about 1.0 ml/min.
  • the maleate salt of compound of formula II, 20 kg, (wherein Ar represents benzyl, Et represents ethyl group; and X and Y are both hydrogen) was suspended in DM water and its free base was extracted into dichloromethane after adjusting the pH to 8.0-8.5 with liquor ammonia.
  • the dichloromethane layer was washed with water, charcoalized, concentrated and the residue stripped off with ethanol.
  • the residue was taken up in 80 1 of ethanol, and 4.3 1 of concentrated hydrochloric and 4 kg of 5%Pd/C (50% wet) were added.
  • the mixture was subjected to catalytic hydrogenolysis with hydrogen gas for 5,0 hours at 35-4O 0 C at 0.5 kg/sq.cm of pressure, cooled and the catalyst was filtered.
  • the filtrate was charcoalized and subjected to distillation at 45-5O 0 C under reduced pressure to remove ethanol.
  • the residue was repeatedly stripped with dichloromethane until the water content of the residue was below 1.0 %.
  • the residue was finally degassed and stripped with acetone. To the residue thus obtained was added acetone and the mixture stirred at 25-3O 0 C for 30 minutes and seeded with pure quinapril hydrochloride.
  • HPLC analysis was carried out by using HPLC method as described above.

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Abstract

The present invention provides a process for preparation of substantially pure 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, compound of formula I or its pharmaceutically acceptable salt comprising: a) subjecting compound of formula II or acid addition salt thereof to hydrogenolysis in aqueous medium in the presence of an acid; wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl group and X and Y are independently selected from the group consisting of hydrogen, (C1-C3)-alkyl or O-(C1-C3)-alkyl or X and Y can be linked together to form a cyclic group -O(CH2)n-O-, wherein n =1or 2. b) extracting the product from the reaction mixture with water immiscible organicsolvent to form an organic extract. c) isolating the compound of formula I or its solvate as a pharmaceutically acceptable salt thereof.

Description

A PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE 1,2,3,4- TETRAHYDROISOQUINOLINE-S-CARBOXYLIC ACID DERIVATIVES
FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of substantially pure l ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives, compound of formula I and pharmaceutically acceptable salt thereof, wherein Et represents ethyl group; and X and Y are independently selected from the group consisting of hydrogen, (C|-C.3)-alkyl or 0-(Ci- C3)-alkyl. The compound of formula I is useful in therapy for the treatment of hypertension.
Figure imgf000002_0001
Formula I
Particularly, the present invention relates to a process for the preparation of compound of formula Ia, wherein X and Y, both are H, commonly known as quinapril and compound of formula Ib, wherein X and Y both are OCH3, commonly known as moexipril.
Figure imgf000002_0002
Formula Ia Formula Ib
BACKGROUND OF THE INVENTION:
United States Patent No. 4,344,949 (the '949 patent; Indian reference not available) discloses compound of formula I and process for preparation thereof from its esters, namely lower alkyl esters, arylmethyl ester or trimethylsilyl ester. The preparation of compound of formula I from its arylmethyl ester, compound of formula II wherein Ar represents phenyl; Et, X and Y are as defined above, is carried out by catalytic hydrogenolysis of the hydrochloride salt of compound of formula II with 20% palladium on charcoal in tetrahydrofuran. After completion of the reaction the compound of formula I is precipitated by addition of 10 fold quantities of ether.
Figure imgf000003_0001
Formula II
The process of the '949 patent has several disadvantages which makes it commercially unviable.
(a) It requires high concentration of palladium (20%) on charcoal which is expensive and uses large quantities of inflammable solvents like tetrahydrofuran and ether.
(b) The yield of the compound Ia is only 56%, and the purity of the compound is not disclosed.
(c) The preparation of hydrochloride salt of compound of formula II requires the use of dry HCl gas which is not convenient for large scale preparations.
United States Patent No 4,761,479 (the '479 patent; Indian reference not available) discusses the preparation of quinapril; the synthetic step involving removal of ester group results in impurity formation to the extent of 10-30%, namely the diketopiperazine impurity and two other unidentified impurities. The diketopiperazine impurity, a compound of formula A,
Figure imgf000004_0001
Formula A is difficult to remove and the crude quinapril is not purifiable by conventional organic chemistry techniques. The '479 patent teaches the preparation of crystalline quinapril hydrochloride from its corresponding 1,1 -dimethyl ethyl ester, making acetonitrile solvate thereof as an intermediate.
United States Patent No. 6,617,457 (the '457 patent; Indian reference not available) discloses process for preparation of compound of formula Ia by hydrogenolysis of compound of formula II (X and Y are both H) with Pd/C in an alcoholic solvent in the presence of concentrated hydrochloric acid. In the workup of the reaction, the catalyst is filtered off, solvent is removed by distillation followed by repeated addition of toluene and removal of solvent by vacuum distillation. The quinapril hydrochloride is isolated in the form of a toluene solvate. The toluene solvate is treated with a class 3 solvent to get the corresponding solvate which is then dried to obtain quinapril hydrochloride.
PCT publication Number WO 2004/054980 (the '980 application) discloses process for preparation of compound of formula Ia by hydrogenolysis of compound of formula II (X and Y are both H) with Pd/C in an alcoholic solvent in the presence of 35% hydrochloric acid. After completion of reaction the catalyst is filtered off and the filtrate is evaporated to give crude quinapril hydrochloride. It is then subjected to further purification by repeated extractions with dichloromethane and concentration followed by formation of a nitroalkane solvate and drying to give quinapril hydrochloride, reportedly in 65 % yield only. UK Patent application No. GB 2095252A discloses catalytic hydrogenolysis of compound of formula II (X and Y are both H) with hydrogen and Pd/C in elhanol. After completion of reaction the catalyst is filtered, the solvent concentrated in vacuo, and the product partitioned between ether and 2N HCl followed by lyophilization. This process has the disadvantage that the compound of formula I formed in this reaction as free base is unstable and partially converts to the diketopiperazine impurity, a compound of formula A. This results in quinapril in yield of only 37 %. Further, lyophilization on industrial scale being energy intensive renders the process economically unviable.
These prior art processes reveal that the synthesis as well as isolation of compound of formula I is a difficult process since the product as well as the starting material, compound of formula II are prone to degradation to give impurities, namely, diketopiperazine impurity, a compound of formula A; diacid impurity, a compound of formula B and ethyl diester impurity, a compound of formula C,
Figure imgf000005_0001
Formula A Formula B
Figure imgf000005_0002
Formula C wherein Et represents ethyl group, X and Y are independently selected from the group consisting of hydrogen, (Ci-C3)-alkyl or O-(Ci-C3)-alkyl and other uncharacterized impurities.
Once formed, these impurities are difficult to remove by conventional separation techniques, including fractional crystallization, thereby reducing the yield and purity of final product. The key to tackle this problem would be to employ conditions for reaction and product isolation which would minimize the formation of key impurities i.e. compounds of formulae A, B and C.
The impurities diketopiperazine, compound of formula A, the diacid, compound of formula B and ethyl diester, compound of formula C, may be formed due to various reaction conditions used in the synthesis and isolation process.
The compound of formula I is a sensitive molecule and is unstable in its free base form. When the side chain nitrogen is unprotonated it undergoes facile intramolecular cyclization to give diketopiperazine impurity, compound of formula A. Therefore the arylmethyl ester, compound of formula II is first protonated by converting into hydrochloride with concentrated HCl and then subjected to hydrogeno lysis in an alcoholic solvent in some of the prior art processes described vide-siφra. However since the hydrochloride salt of compound of formula I is soluble in water as well as in alcohol, the process of isolation of the compound of formula I in prior art processes involves removal of these solvents from the reaction mixture by the process of distillation. This workup procedure is time consuming and energy intensive because of the composition of the reaction mixture. The generated product, compound of formula I is thus subjected to thermal conditions in aqueous-alcoholic acidic medium for long durations, especially on commercial scale preparations. Heating under aqueous acidic condition can partially hydrolyze the side chain ester moiety of compound of formula I, to give the diacid impurity, compound of formula B. Also the other impurity, viz. ethyl diester, compound of formula C, forms during removal of alcohol from the hydrogenolysis medium by distillation, by esterification of compound of formula 1, in presence of acid.
In these prior art processes, after initial removal of the hydrogenolysis solvent system by distillation, another solvent like dichloromethane or toluene is added followed by distillation. This process is repeated number of times so that the water and alcohol traces are completely removed, thus subjecting the product to further heating. These prolonged thermal conditions during concentration of solution or thermal drying of solvates may lead to increased formation of the diketopiperazine impurity, compound of formula A.
Moreover, when we repeated the hydrogenolysis reaction of formula II (X and Y are both H) in ethanol on a few kilogram scale in a reactor, we observed that stripping of solvent system containing some amount of water from the added concentrated hydrochloric acid was time consuming thereby leading to the formation of significant amounts of the diketopiperazine impurity, compound of formula A; diacid impurity, compound of formula B and ethyl diester impurity, compound of formula C, along with other impurities as compared to when the reaction was carried out on a few gram scale in laboratory. Thus we find that the processes of '457 and '980 are not really viable for commercial scale preparations.
The reported methods of synthesis of compound of formula I involving hydrogenolysis of compound of formula II in alcohol and acid when carried on an industrial scale lead to the formation of significant amount of diketopiperazine impurity, compound of formula A; diacid impurity, compound of formula B and ethyl diester impurity, compound of formula C, and are low yielding, time consuming and involve use of inflammable solvents.
Thus there is a need in the state of art for a process that would minimize the formation of impurities and provides substantially pure l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives, compound of formula I or a pharmaceutically acceptable salts thereof besides circumventing the other drawbacks of the prior art. We have now developed a safe, high yielding, commercially viable process for the preparation of substantially pure compound of formula I.
As used herein, the term substantially pure compound of formula I or pharmaceutically acceptable salts thereof means a compound of formula I or pharmaceutically acceptable salts thereof, which has impurity A in less than 0,5%, impurity B in less than 0.5% and impurity C in non-detectable amounts; preferably impurity A is less than 0.2%, impurity B is less than 0.2% and 0% impurity C, as measured by HPLC (high performance liquid chromatography) analysis.
The present invention provides a safe and convenient process for the preparation of compound of formula I or a salt thereof by hydrogenolysis of compound of formula II or acid addition salt thereof in an aqueous medium, in presence of acid. Typically, after hydrogenolysis the catalyst is filtered off and product is extracted from the reaction mixture with water immiscible organic solvent, thereby avoiding removal of hydrogenolysis solvent system by heating. Thus the process avoids conditions that are detrimental to the product quality, i.e. heating of the reaction mixture with a potentially pro-impurity forming composition of acid, alcohol and water. The end result is minimization of the formation of impurities, especially compounds of formulae A & B, and prevention of impurity C, to obtain substantially pure compound of formula I or a salt thereof.
The process of the present invention thus has several advantages
(a) It isolates the compound of formula I by extracting in an organic solvent and thereby avoiding the step of heating the reaction mixture containing the product in an aqueous acidic medium. This leads to the formation of substantially pure compound of formula I, which is substantially free of diketopiperazine impurity, compound of formula A; diacid impurity, compound of formula B and ethyl diester impurity, compound of formula C.
(b) It gives high yield of compound of formula I. (c) The workup is simple and less time consuming, as it does not involve stripping of hydrogenolysis solvent system.
(d) Hydrogenolysis is carried out in aqueous medium hence large scale handling of palladium is safe.
(e) The process is more robust and is especially suitable for commercial scale manufacture.
SUMMARY OF THE INVENTION
The present invention in one aspect provides a process for preparation of substantially pure l,2,3,4-tetrahydiOisoquinoline-3-carboxylic acid, compound of formula I or its pharmaceutically acceptable salt comprising: a) subjecting compound of formula II or acid addition salt thereof to hydrogenolysis in aqueous medium in the presence of an acid;
Figure imgf000009_0001
Formula I Formula II
wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl group; and X and Y are independently selected from the group consisting of hydrogen, (C[-C3)-alkyl or O-(Ci-C3)-alkyl or X and Y can be linked together to form a cyclic group — O(CH2)n-O-, wherein n =lor 2. b) extracting the product from the reaction mixture with water immiscible organic solvent to form an organic extract. The present invention in one aspect provides a process for industrial scale preparation of substantially pure l,2,3,4-tetralαydroisoquinoline-3-carboxylic acid, compound of formula I or pharmaceutically acceptable salt thereof comprising: a) subjecting compound of formula II or acid addition salt thereof to hydrogenolysis in aqueous medium in the presence of an acid;
Figure imgf000010_0001
Formula I Formula II wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl group; and X and Y are independently selected from the group consisting of hydrogen, (Ci-C3)-alkyl or O-(Ci-C3)-alkyl or X and Y can be linked together to form a cyclic group -0(CH2)Ii-O-, wherein n =lor 2. b) extracting the product from the reaction mixture with water immiscible organic solvent and c) isolating the compound of formula I or its solvate as a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a safe and convenient process for the preparation of substantially pure 1,2,3,4— tefrahydroisoquinoline-3-carboxylic acid, compound of formula I or pharmaceutically acceptable salt thereof from compound of formula II or acid addition salt thereof.
Figure imgf000011_0001
Formula I ' Formula II wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl group wherein phenyl ring is substituted with one or more halogen, O-(CpC4)-alkyl or haloalkoxy group containing Ci-C4 alkyl, for example, -OCF3 group and the like and X and Y are independently selected from the group consisting of hydrogen, (Ci-C3)-alkyl or O-(C-i-C3)-alkyl or X and Y can be linked together to form a cyclic group — 0(CH2)n-0-, wherein n =l or 2.
In one embodiment, the present invention provides a process for preparation of substantially pure l,2,3,4-tetraliydroisoquinoline-3-carboxylic acid, compound of formula I or its pharmaceutically acceptable salt comprising: a) subjecting compound of formula II or acid addition salt thereof to hydrogenolysis in aqueous medium in the presence of an acid;
Figure imgf000011_0002
Formula I Formula II
wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl group and X and Y are independently selected from the group consisting of hydrogen, (Ci-C3)-alkyl or G-(Ci-C3)-alkyl or X and Y can be linked together to form a cyclic group -0(CH2)n-0-, wherein n =lor 2. b) extracting the product from the reaction mixture with water immiscible organic solvent to form an organic extract.
In a preferred embodiment the compound of formula I or its solvate is isolated as a pharmaceutically acceptable salt thereof by removing the solvent from said organic extract by any method known in the art like removal of solvent by heating.
In another embodiment the present invention provides a process for industrial scale preparation of substantially pure l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid compound of formula I or pharmaceutically acceptable salt thereof comprising a) subjecting compound of formula II or acid addition salt thereof to hydrogenolysis in aqueous medium in the presence of an acid;
Figure imgf000012_0001
Formula I Formula II wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl group and X and Y are independently selected from the group consisting of hydrogen, (C1-C3)-alkyl or O-(Ci-C3)-alkyl; b) extracting the proditct from the reaction mixture with water immiscible organic solvent and c) isolating the compound of formula I or its solvate as a pharmaceutically acceptable salt thereof. The batch size for industrial scale is preferably at least about 0.5 kg. Example 1 illustrates such an industrial process, which prepares the compound of formula I in a batch having about 10 kg.
In one preferred embodiment the present invention provides a process for the preparation of substantially pure ,l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, compound of formula I or pharmaceutically acceptable salt thereof, wherein X and Y both are H.
In one preferred embodiment the present invention provides a process for the preparation of substantially pure l,2,3,4-tetrahydrojsoquinoline-3-carboxylic acid, compound of formula I or pharmaceutically acceptable salt thereof, wherein X and Y both are OCH3.
The aqueous medium for hydrogenolysis maybe selected from water or a mixture thereof with a solvent selected from ketones such as acetone, methyl ethyl ketone and the like; amides such as dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, ureas and the like, nitriles such as acetonitrile and the like.
In a preferred embodiment, the hydrogenolysis medium is water and acetone mixture. Any suitable volume ratio of water and acetone may be used depending on the amount of the compound of formula II to be subjected to hydrogenolysis. A suitable quantity and composition of water and acetone solvent mixture to be used for hydrogenolysis may be determined by one skilled in the art. The quantity and composition is chosen such that the compound of formula II that is to be subjected to hydrogenolysis dissolves to form a homogeneous solution at the temperature at which the hydrogenolysis reaction is carried out.
In one preferred embodiment the present invention provides a process for preparation of substantially pure 1,2,3,4— tetrahydroisoquinoline-3-carboxylic acid, compound of formula I or pharmaceutically acceptable salt thereof, wherein X and Y both are H, comprising subjecting a compound of formula II or acid addition salt thereof, wherein X and Y both are H, to hydrogenolysis in aqueous medium in the presence of an acid, wherein the aqueous medium comprises of water and acetone mixture in the volume ratio of 1: 1.
The hydrogenolysis of compound of formula II in aqueous medium may preferably be carried out in presence of concentrated HCl or solution of hydrogen chloride in a suitable solvent.
The hydrogenolysis in aqueous medium may be carried out using any suitable hydrogen source, for example, hydrogen gas at a pressure between 0-20 bar and at a temperature between -20 to 50°C in the presence of any suitable hydrogenation catalyst, for example, 10% palladium on charcoal.
Any suitable water immiscible organic solvent can be used for the extraction of compound of formula I obtained by hydrogenolysis of compound of formula II. Preferably, a non-protic and volatile organic solvent for example, aliphatic halogenated hydrocarbons such as dichloromethane, ethylene dichloride or chloroform may be used.
The pharmaceutically acceptable salt of compound of formula I may be selected from hydrochloride, hydrobromide, sulfate, nitrate, acetate, fumarate, maleate, citrate and the like. The acid addition salts of compounds of formula II may be selected from hydrochloride, maleate, hydrobromide, sulfate, nitrate, acetate, fumarate, maleate, citrate and the like.
In a preferred embodiment the present invention provides substantially pure 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, compound of formula I which is substantially free of impurities represented by formulae A, B and C and solvates and salt thereof.
In one preferred embodiment the present invention provides substantially pure 1,2,3,4— tetrahydroisoquinoline-3-carboxylic acid, compound of formula I which contains a compound of formula A in less than 0.5%, a compound of formula B in less than 0.5% and compound of formula C is in non-detectable amount as measured by HPLC analysis.
In one preferred embodiment the present invention provides substantially pure 1,2,3,4- tetrahydiOisoquinoline-3-carboxylic acid, compound of formula I which contains a compound of formula A in less than 0.5%, a compound of formula B in less than 0.5% and compound of formula C is 0% as measured by HPLC analysis.
In one preferred embodiment the present invention provides substantially pure 1 ,2,3,4— tetrahydroisoqumoline-3-carboxylic acid, compound of formula I which contains a compound of formula A in less than 0.2%, a compound of formula B in less than 0.2% and compound of formula C is in non-detectable amount as measured by HPLC analysis.
In one preferred embodiment the present invention provides substantially pure 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, compound of formula I which contains a compound of formula A in less than 0.2%, a compound of formula B in less than 0.2% and compound of formula C is 0% as measured by HPLC analysis.
In a typical work up, after completion of hydrogenolysis the catalyst is removed by filtration. The reaction mixture is then extracted with a water immiscible organic solvent. The compound of formula I or its solvate or a pharmaceutically acceptable salt thereof, may be isolated by removing the organic solvent from the extract, preferably under vacuum at the temperature preferably below 5O0C. If desired the isolated compound of formula I or a pharmaceutically acceptable salt thereof can be dissolved in another organic solvent and crystallized out as a solvate thereof, for example, acetone solvate or acetonitrile solvate, optionally by seeding if required, which may then be converted to a compound of formula I or a pharmaceutically acceptable salt thereof by drying the product, preferably under vacuum at a temperature preferably below 500C. The step of formation of solvate of compound of formula 1 may be repeated if desired. In a preferred embodiment, a compound of formula Ia, quinapril or a pharmaceutically acceptable s.alt is prepared by subjecting the compound of formula II (wherein X and Y are both H) to hydrogenolysis in an aqueous medium containing acetone in the presence of a hydrogenation catalyst like palladium on carbon (Pd/C), hydrogen source like hydrogen gas and hydrochloric acid at a temperature of about 4O0C. After completion of the reaction, the catalyst is removed by filtration and the aqueous reaction mixture is extracted with a water immiscible organic solvent like dichloromethane. The organic solvent is removed by heating under vacuum, preferably at / below 40°C. The residue is dissolved in acetone and the product is crystallized out, preferably by cooling to about 0 to about 100C, filtered and dried under vacuum, preferably below a temperature of 5O0C to obtain quinapril or a pharmaceutically acceptable salt thereof.
The process of the present invention provides substantially pure 1,2,3,4— tetrahydroisoquinoline-3-carboxylic acid derivatives, compound of formula I, with purity greater than 98%, as determined by HPLC.
The compound of formula II may be prepared by a method known to those skilled in the art such as United States Patent No. 4,344949, which is incorporated herein by reference.
Throughout the specification and the claims which follow, unless the context requires otherwise, the phrase 'compound of formula F and 'compound of formula IF will be understood to include their respective pharmaceutically acceptable salts or acid addition salts.
The examples that follow do not limit the scope of the present invention and are included as illustrations.
EXAMPLES:
Example 1
Preparation of compound of formula I (wherein X and Y are H)
The maleate salt of compound of formula II, 10 kg (wherein Ar represents phenyl, Et represents ethyl group; and X and Y are both hydrogen) was suspended in DM water, and its free base was extracted into dichloromethane after adjusting pH to 8.0 to 8.5 with 10% sodium carbonate solution. The dichloromethane extract was concentrated under reduced pressure and degassed under vacuum. The residue was taken up in a mixture of 20 litres of DM water and 20 litres of acetone and 1.0 kg 5%Pd/C (50% wet) and 4 litres of 35% hydrochloric acid were added. The reaction mass was subjected to catalytic hydrogenolysis with hydrogen gas for 5.0 hours at 35-4O0C at 0.5 kg/sq.cm pressure, and the catalyst was filtered. The filtrate was extracted with dichloromethane, the extract concentrated at below 350C under reduced pressure, and resulting residue was stripped with acetone under vacuum. The residue thus obtained was stirred with acetone, and cooled to 5-1O0C. The crystallized product was filtered and dried at 450C in a vacuum oven to obtain 6.22 kg of quinapril hydrochloride, compound of formula I wherein Et represents ethyl group; and X and Y are hydrogen, as a solvate of acetone, having purity 98.93% as determined by HPLC, and containing 0.09% of compound of formula A, 0.11 % of compound of formula B, and compound of formula C was not detected.
HPLC analysis method for compound of formula I (wherein X and Y are H) and related substances
Buffer:
Transfer 0.92 g of heptanesulphonic acid sodium salt into a 1000 ml volumetric flask.
Dissolve in and dilute upto mark with HPLC grade water. Add ImI of triethylamine and mix well. Adjust the pH of the solution to 2.0 ± 0.1 with perchloric acid.
Mobile phase:
Mix buffer solution and acetonitrile in the ratio of 6 : 4. Filter and degas prior to use. Diluent:
Transfer 2.88 g of ammonium dihydrogenorthophosphate into a 1000 ml volumetric flask, dissolve in and dilute up to mark with HPLC grade water. Adjust pH to 6.5 with ammonia solution. Mix 300 ml of this solution mix with 200 ml of acetonitrile. Filter and degas prior to use.
Sample preparation :
Transfer about 20 mg accurately weighed sample into a 10 ml volumetric flask. Dissolve in and dilute up to mark with diluent .
System suitability solution .•
Transfer about 10 mg of accurately weighed sample into a 100 ml volumetric flask.
Dissolve in and dilute up to mark with diluent.
Chromatographic system :
The liquid chromatograph is equipped with a 214 nm UV detector and 25cm x 4.0mm, 5μ column that contains Superspher® RP 8. The flow rate is maintained at about 1.0 ml/min.
Procedure:
Inject 10 μl of the system suitability solution into the system and record the chromatograms upto 80 min. Calculate the tailing factor of quinapril peak. It should not be more than 2 and number of theoretical plates should not be less than 2000.
Inject 10 μl of the sample preparation into the system and record the chromatogram upto 80 min. The retention time of quinapril is about 21.5min. Retention times of impurities A, B and C are about 30.6, 8.61 and 69.3 min, respectively. The amount of related substances are calculated by area normalization method. Comparative Example
Preparation of compound of formula I (wherein X and Y are H) (Hydrogenolysis in ethanol)
The maleate salt of compound of formula II, 20 kg, (wherein Ar represents benzyl, Et represents ethyl group; and X and Y are both hydrogen) was suspended in DM water and its free base was extracted into dichloromethane after adjusting the pH to 8.0-8.5 with liquor ammonia. The dichloromethane layer was washed with water, charcoalized, concentrated and the residue stripped off with ethanol. The residue was taken up in 80 1 of ethanol, and 4.3 1 of concentrated hydrochloric and 4 kg of 5%Pd/C (50% wet) were added. The mixture was subjected to catalytic hydrogenolysis with hydrogen gas for 5,0 hours at 35-4O0C at 0.5 kg/sq.cm of pressure, cooled and the catalyst was filtered. The filtrate was charcoalized and subjected to distillation at 45-5O0C under reduced pressure to remove ethanol. The residue was repeatedly stripped with dichloromethane until the water content of the residue was below 1.0 %. The residue was finally degassed and stripped with acetone. To the residue thus obtained was added acetone and the mixture stirred at 25-3O0C for 30 minutes and seeded with pure quinapril hydrochloride. The mass was cooled to 5-1O0C, then filtered and dried at 45-5O0C in vacuum oven at 450C to obtain 8.3 kg of compound of formula I (wherein X and Y are H) associated with a solvate of acetone, having purity 93.51% as determined by HPLC, and 0.3% of compound of formula A, 2.16% of compound of formula B, and 1.87% compound of formula C.
The HPLC analysis was carried out by using HPLC method as described above.

Claims

We claim
1. A process for preparation of substantially pure l,2,3,4-tetrahydroisoquinoline-3- carboxylic acid, compound of formula I or its pharmaceutically acceptable salt comprising: a. subjecting compound of formula II or acid addition salt thereof to hydrogeno lysis in aqueous medium in the presence of an acid;
Figure imgf000020_0001
Formula I Formula II
wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl group and X and Y are independently selected from the group consisting of hydrogen, (Ci-C3)-alkyl or O-(Ci-C3)-alkyl or X and Y can be linked together to form a cyclic group — O(CH2)n-O-5 wherein n =lor 2. b. extracting the product from the reaction mixture with water immiscible organic solvent to form an organic extract.
2. The process as claimed in claim 1, wherein the compound of formula I or its solvate is isolated as a pharmaceutically acceptable salt thereof by removing the solvent from said organic extract.
3. The process as claimed in claim 1, wherein X and Y both are H.
4. The process as claimed in claiml, wherein X and Y both are OCH3
5. The process as claimed in claiml, wherein the resultant substantially pure 1 ,2,3,4- tetrahydiOisoquinoline-3-carboxylic acid, compound of formula I is substantially free of impurities represented by formulae A, B and C:
Figure imgf000021_0001
Formula A Formula B
Figure imgf000021_0002
Formula C
and solvates or salts thereof.
6. The process as claimed in claim 5, wherein the resultant substantially pure 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, compound of formula I or pharmaceutically acceptable salts thereof contains a compound of formula A in less than 0.5%, a compound of formula B in less than 0.5% and compound of formula C is in non-detectable amount as measured by HPLC analysis.
7. The process as claimed in claim 5, wherein the resultant substantially pure 1,2,3,4- tetrahydiOisoquinoline-3-carboxylic acid, compound of formula I or pharmaceutically acceptable salts thereof contains a compound of formula A in less than 0.2%, a compound of formula B in less than 0.2% and compound of formula C is in non-detectable amount as measured by HPLC analysis.
8. The process for industrial scale preparation of substantially pure 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid compound of formula I or pharmaceutically acceptable salt thereof comprising a) subjecting compound of formula II or acid addition salt thereof to hydrogeno lysis in aqueous medium in the presence of an acid;
Figure imgf000022_0001
Formula I Formula II
wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl group and X and Y are independently selected from the group consisting of hydrogen, (CpC3)-alkyl or O-(Ci-C3)-alkyl or X and Y can be linked together to form a cyclic group -0(CH2)Ii-O-, wherein n =lor 2. b) extracting the product from the reaction mixture with water immiscible organic solvent and c) isolating the compound of formula I or its solvate as a pharmaceutically acceptable salt thereof.
9. The process as claimed in claim 8, wherein X and Y both are H.
10. The process as claimed in claim 8, wherein X and Y both are OCH3.
11. The process as claimed in claim 8, wherein the resultant, substantially pure l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, compound of formula I is substantially free of impurities represented by formulae A, B and C:
Figure imgf000023_0001
Formula A Formula B
Figure imgf000023_0002
Formula C and solvates or salts thereof.
12. The process as claimed in claim 11, wherein the resultant substantially pure 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid compound of formula I or pharmaceutically acceptable salts thereof contains impurity A in less than 0.5%, impurity B in less than 0.5% and impurity C in non-detectable amount as measured by HPLC analysis-
lS. The process as claimed in claim 11, wherein the resultant substantially pure 1,2,3,4- tetrahydroisoquinoline-S-carboxylic acid compound of formula I or pharmaceutically acceptable salts thereof contains impurity A in less than 0.2%, impurity B in less than 0.2% and impurity C in non-detectable amount as measured by HPLC analysis.
PCT/IN2006/000414 2005-10-14 2006-10-13 A process for the preparation of substantially pure 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives WO2007069268A2 (en)

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US4344949A (en) * 1980-10-03 1982-08-17 Warner-Lambert Company Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids
EP0065301A1 (en) * 1981-05-18 1982-11-24 Merck & Co. Inc. Isoquinoline carboxylic acid derivates, process for preparing and pharmaceutical composition containing the same
US4761479A (en) * 1987-03-30 1988-08-02 Warner-Lambert Company Crystalline quinapril and a process for producing the same
ES2122941B1 (en) * 1997-05-29 1999-07-01 Esteve Quimica Sa PROCEDURE FOR OBTAINING QUINAPRIL CHLORHYDRATE AND SOLVATES USEFUL FOR THE ISOLATION AND PURIFICATION OF QUINAPRIL CHLORHYDRATE.

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