KR870002018B1 - Process for preparation of 9-carbamoyl-9-(3-aminopropyl)fluorenes - Google Patents

Abstract

The title compds. (I) are produced from catalytic hydrogenation (1-4 atm) of (II) in the presence of strong acid (more acidic than glacial acetic acid, pka<2) i.e. benzosulfonic acid, Obromobenzoic acid, HF, HCl, H3PO4 etc., In the form ula, R and R1=H, C1-4 alkyl, F or Cl; R2 and R3=H or C1-6 alkyl. The rxn. is performed at ambient temp. for 2-24 hrs. The product easily is sepd. by filtering and evapg. from rxn. mixt., and can be sepd. as acid addn. salt.

Description

Process for preparing 9-carbamoyl-9- (3-aminopropyl) fluorene

The present invention relates to a novel process for the preparation of 9-carbamoyl-9- (3-aminopropyl) fluorene of the general formula (I) having useful antiarrhythmic activity.

In the above formula

R and R ¹ are each hydrogen, C ₁ -C ₄ alkyl, fluoro or chloro,

R ² and R ³ are each hydrogen or C ₁ -C ₆ alkyl.

Recently, groups of 9-aminoalkylfluorenes are known to have excellent arrhythmic therapeutic activity (see, for example, US Pat. Nos. 4197313 and 4277495). 9-carbamoyl-9-aminoalkylfluorene is one of the most interesting compounds and one of this group. That is, 9-carbamoyl-9- (3-isopropylaminopropyl) -fluorene is commonly known as indecaidide.

A process for preparing 9-carbamoyl-9-(-aminopropyl) fluorene, an intermediate in the synthesis of indecainide, is described in US Pat. No. 4,428,170, which describes 9-carbamoyl-9- (2 Hydrogenation of cyanoethyl) fluorene. Although the hydrogenation reaction may be used an organic solvent such as ethanol if necessary, it is known that it is most suitable to perform in an acidic medium, most preferably glacial acetic acid.

The hydrogenation process described in US Pat. No. 4428170 has been found to form significant amounts of fluorene dimers and trimer by-products, compounds of formulas (III) and (IV).

Removal of these by-products has proved extremely difficult and typically these by-products are formed in secondary reactions and can be found in the final product.

It is an object of the present invention to provide an improvement in the process for the hydrogenation of 9-carbamoyl-9- (2-cyanoethyl) fluorene. An improvement by the present invention is to reduce the amount of the aforementioned fluorene dimers and trimer by-products prepared to enable the formation of pure medicaments.

In particular, the present invention relates to improvements in the process of converting cyanoethylfluorene to amino-propylfluorene. The present invention provides a process for the preparation of a compound of formula (I) comprising catalytic hydrogenation of a compound of formula (II), wherein the reaction is carried out in the presence of an acid medium stronger than glacial acetic acid. To provide.

In the above formula

R and R ¹ , R ² and R ³ are as described above.

In a preferred embodiment of the invention the hydrogenation reaction is carried out in the presence of trifluoroacetic acid. In another preferred embodiment the hydrogenation reaction is carried out in the presence of an inorganic acid such as hydrochloric acid.

The process according to the invention is carried out by catalytic hydrogenation of 9-carbamoyl-9- (2-cyanoethyl) fluorene in an acid medium stronger than glacial acetic acid. As pointed out in US Pat. No. 4428170, the hydrogenation of cyano groups of cyanoethyl fluorene can be carried out using conventional hydrogenation catalysts such as platinum, palladium, nickel, rhodium and ruthenium. Will typically be carried out under hydrogen pressure of about 1 to about 4 atmospheres at a temperature of about 20 to about 70 ° C.

The hydrogenation process of the present invention can be carried out mainly in organic solvents: what is needed is that an acid stronger than glacial acetic acid must be present in the reaction mixture at least about 1 molar equivalent. Organic solvents that can be used include alcohols, ethers, aromatic compounds, amides as well as mixtures of organic or inorganic acids and acids. For example, this process is easily performed in alcohols such as methanol or ethanol, with at least about 1 molar amount of a strong acid such as 12N hydrochloric acid, etc., on reduced cyano-ethylfluorene.

Acids stronger than acetic acid can be used in the process of the invention. Such acids include acids having a pka of less than about 4.75 (glacial acetic acid pka at 25 ° C.). Preferred acids have a pka of less than 2.0, most preferably less than 1.0. Examples of strong acids that can be used in the process of the invention include benzosulfonic acid, one of aminobenzosulfonic acids, ortho or meta-bromobenzoic acid, trichloroacetic acid, chlorobenzoic acid, 2-chlorophenoxyacetic acid, 3-chlorophenoxy Acetic acid, dimethylmalonic acid, dinicotinic acid, diphenylacetic acid, fluorobenzoic acid, formic acid, fluoroacetic acid, glycolic acid, hypofuric acid, 2-hydroxybenzoic acid, 2-iodic benzoic acid, itaconic acid, rutidine acid, maleic acid, Malonic acid, mesaconic acid, methylmalonic acid, naphthalenesulfonic acid, α-naphthoic acid, oxalic acid, O-phthalic acid, quinoline acid, sulfanic acid, α-tartaric acid, trichloroacetic acid, trifluoroacetic acid, 2,4,6- Trihydroxybenzoic acid and similar strong organic acids. Inorganic acids may also be used and examples of such acids are arsenic acid, chromic acid, hydrofluoric acid, hydrochloric acid, iodic acid, nitrous acid, periodic acid, phosphoric acid, pyrophosphate, selenic acid, sulfuric acid and related strong inorganic acids.

Although the mechanism of the process of the invention is not fully understood, the strong acid required for use according to the invention reacts with the primary amino group of 9- (3-aminopropyl) fluorene as it forms to form an acid addition salt. It is believed to be. If the primary amino group is protonated as an acid addition salt, reaction with other reaction intermediates is undesirable because it produces dimers and trimer byproducts.

The hydrogenation process of the present invention is nearly complete within about 2 to about 24 hours when performed under hydrogen pressure of about 1 to about 4 atmospheres at about ambient temperature. 9-carbamoyl-9- (3-aminopropyl) fluorene prepared by this method is easily separated by known methods as necessary. For example, the reaction mixture can be filtered to remove the hydrogenation catalyst and the reaction solvent can be removed from the filtrate, for example by evaporation under reduced pressure. The aminopropylfluorene product can be separated and crystallized with acid addition salts and, if necessary, the salts can be neutralized by reaction with a base such as sodium hydroxide or ammonium hydroxide to produce the desired primary amine. This amine, or acid addition salt, can be alkylated by conventional methods such as those described in US Pat. Nos. 4197313 and 4282170.

Alternatively, in a preferred embodiment of the present invention 9-carbamoyl-9- (3-aminopropyl) fluorene is not isolated, but reacted in situ to react 9-carbamoyl-9- (3-isopropylamino N-alkyl derivatives such as propyl) fluorene are prepared. This alkylation reaction is carried out by neutralizing excess acid first, for example by the addition of a base such as sodium bicarbonate, followed by addition of aldehyde or ketone to the hydrogenation reaction mixture and further hydrogenation of the mixture. The aldehyde or ketone is reacted with the primary amino group of 9-carbamoyl-9- (3-aminopropyl) fluorene to prepare the corresponding schiff base and undergo further hydrogenation to give the desired N-alkyl derivative. Reduced to. For example, 9-carbamoyl-9- (2-cyanoethyl) fluorene may be reacted to the present invention by reaction with hydrogen gas in the presence of a catalyst (e.g. platinum oxide) and a strong acid (e.g. trichloroacetic acid). Hydrogenation can thus produce 9-carbamoyl-9- (3-aminopropyl) fluorene containing little dimer or trimer by-product. The reaction mixture is neutralized by addition of at least about 1 molar amount of a base such as sodium hydroxide. Ketones such as acetone can be added to the neutralized reaction mixture and the mixture can be further hydrogenated to produce 9-carbamoyl-9- (3-isopropylaminopropyl) fluorene. The product thus prepared contains little undesirable by-products and can be separated and purified by conventional methods.

Improvements in the method provided by the present invention will be explained in more detail by the following examples. However, it should not be construed as limiting the invention to these examples.

Example 1

A mixture of 20 g of 5% palladium on charcoal and 100 g of 9-carbamoyl-9- (2-cyanoethyl) fluorene in 560 ml of tetrahydrofuran and 50 ml of water is stirred at 1000 ° C. under 1000 psi of hydrogen for 24 hours. The reaction mixture is filtered and the filtrate is concentrated to dryness to give 93.5 g of a white solid which is identified primarily as a dimer and trimer product. This solid is suspended in 500 ml of acetone and the mixture is stirred at 25 ° C. for 1 hour and then filtered to yield 34 g of a white solid. The filtrate is concentrated to give 50 g of white solid. The white solid is bound and polished in 675 ml of hot tetrahydrofuran. The mixture is filtered and the solvent is removed from the filtrate to give 69.9 g of a white solid with a melting point of 162.5 to 165 ° C. This solid is chromatographed twice on silica gel and eluted with tetrahydrofuran to give an almost pure sample of formula (V).

Analyzes for C ₃₄ H ₃₃ N ₃ O ₂

Theoretic value: C, 79.19: H, 6.45: N8.15

Found: C, 77.17: H, 6.33N, 7.39

8 g of this dimer is added to 150 ml of methanol containing 200 ml of ethyl acetate and 1.8 g of maleic acid. The reaction mixture is heated at 100 ° C. for 1 hour and then cooled. The crystal precipitate was filtered and air dried to obtain 9,9 ′-(iminodi-3,1-propanediyl) bis [9H-fluorene-9-carboxamidel (General Formula VI) having a melting point of 185 to 187 ° C. 9.8 g of Z) -2-butene-dioate (1: 1) are obtained.

Analyzes for C ₃₈ H ₃₇ N ₃ O ₆

Theoretic Value: C, 72.75: H, 5.90: N, 6.65

Found: C, 71.97: H, 6.00: N, 6.40

Example 2

A mixture of 4.0 g of platinum oxide and 15.02 g (57.2 mM) of 9-carbamoyl-9- (2-cyanoethyl) fluorene in 200 ml of glacial acetic acid is shaken at 25 ° C. under hydrogen atmosphere (4 atm) for 3 hours. . 5.0 g (86 mM) of acetone was added to the reaction mixture to dilute and the hydrogenation reaction was continued for an additional 17 hours. The reaction mixture is filtered and the filtrate is concentrated to dryness by evaporation of the solvent under reduced pressure to give 32.0 g of a brown viscous oil. The oil is added to 200 ml of ethyl acetate and 200 ml of ice water and the mixture is diluted by the addition of 400 ml of 6N hydrochloric acid. The aqueous acid layer is separated and alkalized by addition of 110 ml of 50% aqueous sodium hydroxide. The aqueous alkali solution is extracted several times with diethyl ether, the ethereal extracts are mixed, washed with water, dried and the solvent is removed by evaporation to yield 13.4 g (76.1% yield) of the product. The product was 83.4% 9-carbamoyl-9- (3-isopropylaminopropyl) fluorene and 8.2% dimer, N, N-bis, identical to those prepared and shown in Example 1 by high performance liquid chromatography [3- (9-carbamoyl-fluoren-9-yl) propyl] amine.

Example 3

A solution of 10.1 g (38 mM) of 9-carbamoyl-9- (2-cyanoethyl) fluorene in 3.3 ml of 12N hydrochloric acid containing 2.0 g of platinum oxide and 190 ml of glacial acetic acid was subjected to 4 atmospheres of hydrogen at 25 캜 for 6 hours. Shaken in a parr hydrogenator. To the reaction mixture is added 3.1 g (38 mM) of sodium acetate and then neutralized by adding 8.34 ml of acetone. The reaction mixture is shaken for an additional 16 hours under 4 atmospheres of hydrogen. Further 2.75 ml of acetone are added to the reaction mixture and it is shaken for an additional 2 hours under hydrogen. The reaction mixture is filtered and the filtrate is concentrated to 36.0 g of viscous liquid. The liquid is dissolved in 200 ml of water and the aqueous solution is washed with diethyl ether and then alkalinized by the addition of 50% aqueous sodium hydroxide. The alkaline mixture is extracted several times with diethyl ether, the ethereal extracts are combined, washed with water and dried. The solvent was removed by evaporation under reduced pressure to yield 9.6 g (82% yield) of a tan solid.

A solution of 9.4 g of a tan solid in 110 ml of acetone is cooled to 0-5 ° C. and diluted with the addition of 3 ml of 12N hydrochloric acid. The reaction mixture is stirred at 0-5 ° C. for 1 hour and the white precipitate formed is collected by filtration and air dried to yield 7.6 g of product at melting points 191-194 ° C. The resulting product is crystallized with 90 ml of hot (80 ° C.) isopropanol to yield 4.8 g of 9-carbamoyl-9- (3-isopropylaminopropyl) fluorene hydrochloride with a melting point of 205 to 207 ° C. High performance liquid chromatography shows that it consists of at least 97.6% pure product and less than 1% dimer.

Analyzes for C ₂₀ H ₂₅ CIN ₂ O

Theoretic Value: C, 69.65: H, 7.31: N, 8.12

Found: C, 69.84: H, 7.47: N, 7.92

NMR (DMSOd ₆ ): δ1.1 (d, 6H): 2.1 to 3.3 (m, 6H): 3.42 (s, 1H): 6.3 (s, 1H): 7.40 to 8.2 (m, 8H): 8.6 to 9.0 (Broad s, 2H).

Example 4

A solution of 8.66 g of trifluoroacetic acid containing 2.0 g of platinum oxide and 10.1 g of 9-carbamoyl-9- (2-cyanoethyl) -fluorene in 193 ml of glacial acetic acid was carried out in a parf hydrogenation flask under 4 atmospheres of hydrogen for 6 hours. Shake in the middle. The reaction mixture is filtered and the filtrate is concentrated to give 28.6 g of viscous liquid. The liquid is added to 200 ml of ice water and the aqueous mixture is washed with dichloro methane. The aqueous layer is alkalized by addition of 50% aqueous sodium hydroxide and the aqueous alkali solution is extracted several times with dichloromethane. Organic extracts were combined, washed with water, dried and the solvent was removed by evaporation under reduced pressure to give 9.9 g (97%) of a tan solid identified as 9-carbamoyl-9- (3-aminopropyl) fluorene by thin layer chromatography. Yield).

A solution of the product 9.1 in 8.34 ml (6.66 g, 114 mM) of acetone containing 190 ml of ethanol and 2.0 g of 5% palladium on charcoal is shaken for 20 hours at 25 ° C. under 4 atmospheres of hydrogen. The reaction mixture is filtered and the filtrate is concentrated to 13.1 g of viscous liquid. The liquid is added to 200 ml of water and 200 ml of diethyl ether. The aqueous layer is separated, alkalized by addition of 50% sodium hydroxide, and diethyl ether is also extracted several times. The ethereal extracts are combined and extracted with 300 ml of 6N hydrochloric acid and 200 ml of water. The aqueous acid extracts are combined, alkalized and extracted with fresh diethyl ether. The ethereal extracts were combined, washed with water and concentrated to dryness to yield 9.9 g (84.6% yield) of a white solid. The solid is dissolved in 100 ml of cold acetone and the solution is saturated with hydrogen chloride. The mixture is stirred for 45 minutes and filtered to yield 8.0 g (77.8%) of 9-carbamoyl-9- (3-isopropylaminopropyl) fluorene hydrochloride. The product is recrystallized from isopropanol to yield 4.7 g (58.7% yield) of hydrochloride at melting point 206-208 ° C.

High pressure liquid chromatography shows that the product is 100% 9-carbamoyl-9- (3-isopropylaminopropyl) fluorene containing no dimers or trimers.

Analyzes for C ₂₀ H ₂₅ CIN ₂ O

Theoretic Value: C, 69.65: H, 7.31: N, 8.12

Found: C, 69.90: H, 7.44: N8.03

NMR (DMSO d6): δ1.1 (d, 6H): 2.1 to 3.4 (m, 7H): 6.22 (s, 1H): 7.0 (s, 1H), 7.4 to 8.2 (m, 8H): 8.5 to 9.1 (Bros s, 2H).

Example 5

시간 동안 진탕시킨다. 반응 혼합물을 8.34ml의 아세톤 및 6.3g의 나트륨 아세테이트를 함유하는 에탄올 20ml중의 목탄상의 5% 팔라듐 2.0g의 혼합물에 첨가한다. 이 반응 혼합물을 25℃에서 수소 4기압하에 20시간 동안 진탕시킨다. 반응 혼합물을 여과하고 여과물을 농축하여 32.2g의 점성오일을 수득한다. 오일을 200ml의 빙수에 첨가하고 수성혼합물을 50%(ｗ/ｖ)수성 수산화나트륨의 첨가로 알칼리화시킨다. 수성 알칼리 혼합물을 디에틸에테르로 여러번 추출시킨다. 에테르성 추출물을 결합하고 300ml의 6N염산 및 200ml의 물로 추출시킨다. 수성산 추출물을 결합하고 새로운 수산화나트륨의 첨가로 알칼리화시키고 새로운 디에틸 에테르로 추출시킨다. 에테르성 추출물을 결합하고 물로 세척하며 건조시키고 농축건조시켜 11.1g(94.8% 수율)의 생성물을 수득한다. 생성물을 80ml의 아세톤중에 용해시키고 용액을 염화수소로 포화시켜 10.2g(91.8%)의 백색 고형물을 수득한다. 고형물을 이소프로판을 105ml로 결정화시켜 6.8g(66.5%)의 9-카바모일-9-(3-이소프로필아미노프로필)-플루오렌 히드로클로라이드(융점 : 205 내지 208℃)를 수득한다. 고성능 액체 크로마토그래피를 수행하면 생성물중에 이량체 또는 삼량체가 상당량 함유하지 않음을 나타낸다. 원소분석 및 NMR은 실시예 3 및 4의 생성물에 대한 것과 일치하였다.A solution of 8.66 g (76 mM) of trifluoroacetic acid containing platinum oxide 2.0 and 10.1 g (38 mM) of 9-carbamoyl-9- (2-cyanoethyl) fluorene in 190 ml of ethanol was subjected to 4 atmospheres of hydrogen at 25 ° C. Under

Shake for hours. The reaction mixture is added to a mixture of 2.0 g of 5% palladium on charcoal in 20 ml of ethanol containing 8.34 ml of acetone and 6.3 g of sodium acetate. The reaction mixture is shaken at 25 ° C. under 4 atmospheres of hydrogen for 20 hours. The reaction mixture is filtered and the filtrate is concentrated to give 32.2 g of viscous oil. The oil is added to 200 ml of ice water and the aqueous mixture is alkalized by the addition of 50% (dl / v) aqueous sodium hydroxide. The aqueous alkaline mixture is extracted several times with diethyl ether. The ethereal extracts are combined and extracted with 300 ml of 6N hydrochloric acid and 200 ml of water. The aqueous acid extracts are combined and alkalized with the addition of fresh sodium hydroxide and extracted with fresh diethyl ether. The ethereal extracts are combined, washed with water, dried and concentrated to dryness to afford 11.1 g (94.8% yield) of the product. The product is dissolved in 80 ml of acetone and the solution is saturated with hydrogen chloride to yield 10.2 g (91.8%) of white solid. The solid was crystallized to 105 ml of isopropane to afford 6.8 g (66.5%) of 9-carbamoyl-9- (3-isopropylaminopropyl) -fluorene hydrochloride (melting point: 205-208 ° C.). High performance liquid chromatography indicates that the product does not contain significant amounts of dimers or trimers. Elemental analysis and NMR were consistent with those for the products of Examples 3 and 4.

Claims (10)

A process for preparing the compound of formula (I), wherein the compound of formula (II) is catalytically hydrogenated in the presence of an acid medium stronger than glacial acetic acid.

Wherein R and R ¹ are each hydrogen, C ¹ -C ⁴ alkyl, fluoro or chloro: R ² and R ³ are each hydrogen or C ¹ -C ⁶ alkyl. The method of claim 1, wherein the pka of the acid medium is less than two. The method of claim 1 wherein the pka of the acid medium is less than one. The method of claim 1 wherein trifluoroacetic acid is used. The method according to any one of claims 1 to 4, wherein an inorganic acid is used. The method of claim 1 wherein R and R ¹ are both hydrogen. The method of claim 6, wherein R ² and R ³ are both hydrogen. A process for producing a compound of formula (A), wherein the compound of formula (I) is alkylated.

In which R and R^OneAre each hydrogen, C_One-C₄Alkyl, fluoro or chloro, R²And R³Is hydrogen or C, respectively_One-C₆ Alkyl, ipr is isopropyl. 9. A process according to claim 8, wherein the primary amine mentioned is reacted with acetone to give a schiff's base which is reduced to effect alkylation. 10. The process of claim 9, wherein all excess acids are neutralized from the catalytic hydrogenation of nitrile and then alkylated in situ.