TW200540149A - Intermediate compounds - Google Patents

Abstract

The invention relates to a novel process for the preparation of certain cyclopropyl carboxylic acid esters and other cyclopropyl carboxylic acid derivatives; a novel process for the preparation of dimethylsulfoxonium methylide and dimethylsulfonium methylide; to the use of certain cyclopropyl carboxylic acid esters in a process for the preparation of intermediates that can be used in the synthesis of pharmaceutically active entities; and to certain intermediates provided by these processes.

Description

200540149 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a novel method for preparing certain kinds of cyclopropylcarboxylic acid esters and other cyclopropylcarboxylic acid derivatives; and to a novel method for preparing methyl Method for dimethyl sulfoxide hydrazone and methyl dimethyl sulfoxide hydrazone; use of certain kinds of cyclic 2 carboxylic acid esters in the preparation of intermediates that can be used in the synthesis of medically active entities; and related methods Some intermediates provided. [Summary] In the first part, the present invention proposes a method for preparing a compound of formula (I):

(D where: R is a phenyl group containing one or more prime substituents;

Y is OR1, where R1 is a linear alkyl group, a branched alkyl group, a cycloalkyl group, or a substituted bicycloheptyl group (or a phenyl group), and the method includes a compound of formula (η):丄 γ Here R and Υ are both in existence as defined above. (K), and methylated disulfoxide in a solvent. Suitably, the solvent is a polar solvent, and dimethylsulfoxide is preferred. Suitably, the reaction is at -10. 〇-90. (:, Preferably at 25 ° C. Methylation of dimethyl sulfoxide can be carried out by using trimethyl sulfoxide salt and a solid strong base. 102725.doc 200540149 is preferably in solid form in dimethyl sulfoxide. Suitably, the base is a metal oxychloride: a reaction at a temperature or a high temperature to prepare a metal hydride, a shaft. Preferably, ^, such as ㈣H, Jane, or as described above, the test is sodium oxyoxide. In the case of Sanya iodide (without phase transfer contact), the powder is mixed with oxygen oxidized sodium powder at dimethyl 9. min. In addition, the condition of chloroform is mixed with nitrogen at 20-2rc.

The better one is HYDRA, which can be passed through trimethylphosphine (Ilf moth or gaseous) and sodium hydroxide to use phase transfer catalysts, such as bromide tetrazolium tetrazide, in dimethyl thief. N-butyl hydrazone, or prepared with other strong bases, such as alkali metal lice. Compounds of formula (II) can be obtained by using compounds of formula (111): 0

II R_CH = CH- C — 0 nm where R is as defined above, and is prepared by reacting with a suitable gasifying agent in the presence of an inert solvent and a selected catalyst at a temperature of 0-20 ° C. The better , Γ is OR1, the gasification agent is sulfenyl chloride, the inert solvent is toluene, and the catalyst is pyridine. Where appropriate, the reaction temperature is 70 ° C. The resulting acid chloride is then reacted with YH or Y— (Here, γ- is an anion of γ), γ is defined above, and optionally reacts at a high temperature, such as 100 ° C. The compound of formula (III) can be prepared by using standard chemistry, for example, using Compound of formula (IV): 0

II R——C—Η (IV) Here R is defined above, and bσ is fixed with the malonic acid. It is determined to be in contact at a high temperature of 102725.doc 200540149, preferably 50-90 ° C. Compounds of formula (I) can be hydrolyzed with protohydrolysis to produce compounds of formula (V) · 0-qh (V) where R is the meaning above, and those with a better _ group are oxidized by using metal test chlorine Substances such as sodium oxide or sodium hydroxide, or quaternary ammonium hydroxide

Agent, such as water, aqueous alcohol or water / tetrahydrofuran, at ι〇_ι〇〇. . It is removed by alkaline hydrolysis. The best is sodium hydroxide, the solvent is ethanol, and the reaction temperature is 50 ° C. Compounds of formula (V) can be used to produce compounds of formula (VI). 〇η Λ 11 ri wind * c —Cl m where R is as defined above, which is via gasification with sulfinic thoron or other appropriate gasification In the presence of toluene or other appropriate solvents, and the selected catalyst, the better than 疋, in the presence of 0 to 200. 〇 Reaction at temperature. Preferably, the temperature is 65-70 ° C. Compounds of formula (VI) can be used to synthesize compounds of formula (VII): 0 Λ 丨 丨 R — ^ — C—N5 (VII) where R is as defined above, which is obtained by contacting with an alkali metal azide (preferably It is made by reacting in the presence of a phase transfer catalyst (preferably tetra-n-butylammonium bromide), carbolic carbonate Kling solution and a solvent (preferably toluene). Preferably, the reaction temperature g0-10t :. 102725.doc 200540149 A compound of formula (VII) can be used to produce a compound of formula (VIII): (νιπ) Here R is as defined above, which is obtained in toluene at a temperature between and 200 ° C, compared with The best one is rearranged at its reaction temperature, and then the isocyanate S intermediate is reacted with hydrochloric acid at a high temperature, preferably 85_90 ° C, and 70% 0 _ via the compound of formula (Vln) If the pH of the aqueous salt solution is adjusted to 10 or more, the parent amine (free base) of the formula (ιχ) can be released without protonation: R △ ma (IX) where R is as defined above. It can then be converted into salts of other organic or inorganic acids, preferably mandelic acid. Ruler-㈠-mandelate of a compound of formula (Ιχ) can be added by adding mandelic acid to a solution of formula (ιχ) at ambient or high temperature. produce. The preferred temperature is 20 ° C. Where appropriate, the R group is a phenyl group that optionally contains one or more _ prime substituents. Preferably, R is a benzyl group containing-or more 1 atom substituents. More preferably, R is 4-fluorophenyl or 3,4-difluorophenyl. More preferably, Y is D-capoxy, or more preferably, ^ violyloxy. Compounds of formulae (I) to (IX) may exist in different isomer forms (e.g., cis isomers, or non-image isomers). The method of the present invention: a mixture of isomeric forms and all proportions thereof. 4 l02725.d〇 (200540149 In the case where γ is opposite, the compound of formula (I) may be a mixture of non-image isomers and may be isolated by crystallization or chromatography to a formula rich in non-image isomers. (La) Compound:

(Ia) V

Here R and Y are both defined above. Preferably, the crystallization is performed on the compound of formula VII, as described above, and then performed in situ, where the crude reaction mixture is heated until completely or nearly completely dissolved, and then cooled at the rate of the field until formation Sufficient enough: After filtering, the crystals were collected. In addition, 'the dissolution can be carried out in any of the following: for example, hydrocarbons such as heptane, wherein the compound of formula ⑴ is taken into an appropriate amount of solvent, and the extract is heated until it is completely dissolved', and then the appropriate Rate cooling until sufficient crystals of desirable quality are formed. Optionally, before the above crystallization, the organic extract can be extracted with water, dehydrated with magnesium sulfate and filtered. The hydrazone compound can be hydrolyzed to produce a compound of formula (I) by using the above method for hydrolyzing a compound of formula (I) to produce a compound of formula (V):

W OH where R is as defined above. Formula compounds can be used to produce compounds of formula (heart) by using the above method for converting compounds of formula (V) to compounds of formula (VI): 102725.doc -10- 200540149

Here R is as defined above. The compound of formula (Via) can be used to synthesize a compound of formula (Vila) by using the above method for converting a compound of formula (VI) to produce a compound of formula (VII):

(Vli) ^ Here R is as defined above. A compound of formula (Vila) can be used to synthesize a compound of formula (Villa) via the method for converting a compound of formula (VII) to produce a compound of formula (VIII): (VHia) where R is as defined above. The compound of formula (Villa) can be used to synthesize a compound of formula (IXa) by using the above method for transforming a compound of formula (VIII) to produce a compound of formula (IX):

Here R is as defined above. The R-(-)-mandelate salt of the compound of the formula (IXa) can be produced by using the above method for producing the R-(-)-mandelate salt of the compound of the formula (IX). These novel compounds form another part of the invention, in which the invention therefore proposes the formulae (I), (la), (II), (III), (V), 102725.doc as defined above 1! 200540149 (Va), (VI), (Via), (VII), (Vila), (VIII), (Villa), (IX) and (IXa). Particularly preferred compounds include: trans-2 (3,4-difluorophenyl) cyclopropanecarboxylic acid (1R, 2S, 5R) _2_isopropyl_5-methylcyclohexyl ester; trans- (lR, 2R) -2- (3,4-difluorophenyl) cyclopropanecarboxylic acid (1r, 2S, 5R) -2-isopropyl-5 -methylcyclohexyl acetate; Lu (E) -3- (3 , 4-difluorophenyl) -2-acrylic acid (1,28,51〇-2-isopropyl-5-fluorenylcyclohexyl ester; (E) -3_ (3,4-diphenylphenyl) _2 • propionic acid; (E) -3- (3,4-difluorophenyl) _2 · propenyl chloride; trans- (lR, 2R) -2- (3,4-difluorophenyl) cyclopropane Carboxylic acid; trans- (lR, 2R) -2- (3,4-difluorophenyl) cyclopropanecarbonyl chloride; trans- (lR, 2R) -2- (3,4-difluorophenyl) cyclopropane Carbonyl azide; trans- (lR, 2S) -2- (3,4-difluorophenyl) cyclopropylamine; and (2R) _2-hydroxy_2_phenylacetic acid trans- (lR, 2S)- 2- (3,4-difluorophenyl) cyclopropane ammonium salt. [Embodiments] The present invention will be illustrated by the following non-limiting examples. Example 1 This example illustrates (E) -3- (3 Preparation of 4-difluorophenyl) -2-acrylic acid. The mixture of fluorene (1.55 kg) and slightly bite (0.72 kg) was heated to 90. Malonic acid (1 7.6 kg), and then 3,4-difluorobenzaldehyde (12.0 kg) was slowly added over a period of 50 minutes. The reaction mixture was placed at 90 t and then 102725.doc -12-200540149 was stirred 4 Hours and 36 minutes. After adding water (58.5 kg), 32 liters of the pyridine / water mixture was distilled off under reduced pressure from the reactor. The reaction mixture was acidified to ρΗ with 40% of 37% hydrochloric acid (6.4 kg). , And then vigorously cooled to 25. The solid was collected by filtration, washed twice with 1% hydrochloric acid (34.8 liters each time), washed with water (61 liters) for a while, and thoroughly deliquored in the filter. Then after 4 〇 〇c The product was dried under vacuum for 24 hours and 40 minutes to obtain 13.7 kg of crystalline product. Example 2 Refer to this example for illustration (Ε) _3_ (3,4-difluorophenyl) -2-propenesulfonyl chloride Preparation: A mixture of (E) -3- (3,4-monofluorophenyl) -2-acrylic acid (8.2 kg), toluene (74 kg), and thallium (0.18 kg) was stirred and heated to 65. Then, add sulfinic sulfonium gas (7.4 kg) during the minutes. After the addition is complete, stir the reaction for another 2 hours and 15 minutes, using toluene 8.7 kg) diluted. Then, the remaining sulfinous thoron gas, sulfur dioxide, hydrogen chloride and toluene (10 liters) were degassed under reduced pressure, and (E) -3- (3,4-difluorophenyl) -2 was charged. -Propylene chloride (about 9 kg of toluene solution. Example 3 • This example illustrates (E) -3- (3,4_difluorophenyl) -2-acrylic acid (1R, 2S, 5R) _ 2 -iso Preparation of propyl-5-methylcyclohexyl. (E) -3- (3,4-difluorophenyl) _2_propene was added to a solution of L-fluorenol (7.1 kg) / toluene (8.5 kg) over 65 minutes at 65 ° C. Tritium chloride (obtained in Example 2) and Emei (0.11 kg, 2.28 mol). After the addition was completed, the reaction mixture was placed under 65 ° C. and stirred for 4 hours and 40 minutes, cooled to 25 ° C., and stirred for 14 hours. The solution was diluted with toluene (6 kg), followed by a 5% aqueous solution of sodium vaporization (6.4 kg), followed by a 6% aqueous solution of Carmenmannan (6 47 kg), and then sequentially extracted with water (6.i kg). wash. The solvent was distilled off under reduced pressure (20 102725 doc -13-200540149 • liters) and the solution was azeotropically dehydrated. Dimethylarsine (33.9 kg) was added and the remaining toluene was distilled off under reduced pressure to obtain 47.3 kg of (E) -3- (3,4-difluorophenyl) -2-acrylic acid (lR, 2S, 5R) 2-Isopropyl-5-methylcyclohexyl ester (approximately 13.3 kg) / disulfoxide solution. Example 4 This example illustrates a method for preparing methylated dimethyl sulfoxide hydrazone (dimethyl (methylene) fluorenyl-λ6-thiocarbonate). | Sodium hydroxide powder (1.2 kg) prepared by grinding sodium hydroxide pellets in a rotary mill and sieving through a 1 mm metal sieve, and Ehua trimethylphosphine (6.2 kg) were placed in two Formosan (25.2 kg) was mixed in a nitrogen atmosphere at 25 ° C for 90 minutes. This solution was used directly in the preparation of (ir, 2S, 5R) -2-isopropyl-5-fluorenylcyclohexyltrans-2- (3,4-difluorophenyl) cyclopropanesulfonic acid. Example 5 This example illustrates a method for preparing methylated disulfone sulfonium (dimethyl (methylene) _λ 4 · sulfur). • Sodium hydroxide powder (970 mg) prepared by grinding sodium hydroxide pellets in a rotary mill and sieving through a 1 mm metallurgist, and Emei trimethyl nucleus (4.66 g) were placed in dimethyl ether The sulfone (17 ml) was stirred under nitrogen at 20-25 ° C for 10 minutes. This solution was directly used in the preparation of trans_2- (3,4-difluorophenyl) cyclopropanecarboxylic acid (1R, 2S, 5R) -2-isopropyl-5-fluorenylcyclohexylamine. Example 6 This example illustrates the preparation of trans-2- (3,4-diIphenyl) cyclopropanecarboxylic acid (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl ester. The (3,4-difluorophenyl) -2-acrylic acid (111,23,511) _2-isopropyl-5-methyl 102725.doc -14-200540149% is as good as (about 8.6 kg) / disulfoxide (Approximately 27.9 kg) The solution was stirred at 25 ° C for 20 minutes and added to the solution containing amidated dimethylsulfinium (approximately 2.6 kg, as prepared above), sodium iodide ((Magic-3 _ About 42 kg), water (about 500 g) and sodium hydroxide (56, g, 56 g) in a mixture of methylene isocyanide (27.7 kg). The reaction mixture was placed under 25 ×: After stirring for 2 hours and 50 minutes, it was directly used to prepare trans- (111,211) -2- (3,4-difluorophenyl) cyclopropanecarboxylic acid (111,28,511) -2-isopropyl-5- Methylcyclohexyl g. Example 7 This example illustrates trans- (1R, 2R) _2_ (3,4_: fluorophenyl) cyclopropanecarboxylic acid (1 R, 2S, 5R) -2-isopropyl · Preparation of 5-methylcyclohexyl ester. Trans_2_ (3,4_difluorophenyl) acrylic acid (lR, 2S, 5R) -2-isopropyl-5, which was prepared as described in Example 6. -The crude solution of fluorenylcyclohexyl ester was heated from 25 C to 50 ° C with stirring during this period and kept at this temperature for another 1 hour. Then the mixture was stirred for 4 hours Cool from 50t to 35oC with stirring, keep it for 1 hour, then cool to 26 ° C for 4 hours, keep at 26 ° C for 1 hour, and then cool to 19 ° C for 3 hours and keep at 5 hours and 10 minutes at 19 ° C. The product crystallized and was collected by filtration to obtain a crystalline solid (2.7 kg), which was proved to contain trans- (1 汉, 211) -2- (3,4-difluorobenzene ) Cyclopropanecarboxylic acid (lR, 2S, 5R) -2-isopropyl-5-methylcyclohexyl ester (1.99 kg) and trans- (lS, 2S) -2- (3,4-difluorobenzene A mixture of cyclopropanecarboxylic acid (ir, 2S, 5R) -2-isopropyl-5-fluorenylcyclohexyl ester (85 g). Example 8 This example illustrates trans- (111,211) -2 -(3,4-Difluorophenyl) cyclopropanecarboxylic acid (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl ester, another method for preparing the same. 102725.doc -15- 200540149 will Trans-2- (3,4-difluorophenyl) cyclopropanecarboxylic acid (ir, 2S, 5R) -2-isopropyl-5-methylcyclohexyl ester (14.3 kg, 44.4 mol) / heptane (128.6 liters) of the solution was distilled off the n-heptane (8 2 · 5 liters) under reduced pressure. The mixture was then cooled from 34 ° C to 24 ° C over 3 hours and 20 minutes. Then trans- (lR , 2R) -2- (3,4-difluorophenyl) cyclopropanecarboxylic acid (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl ester was seeded and the mixture was allowed to stand for 5 hours Cooled to 0 ° C during 50 minutes. The product obtained by filtration was a crystalline solvent wet solid (7.05 kg), which proved to contain trans- (lR, 2R) -2- (3,4-difluorophenyl) cyclopropanecarboxylic acid (ir, 2S, 5R) 2-Isopropyl 5-methylcyclohexyl ester (4.7 kg) and trans- (is, 2S) -2- (3,4-difluorophenyl) cyclopropane acid (lR, 2S, 5R ) -2-Isopropyl-5-methylcyclohexyl ester (1.1 kg) mixture 0 Example 9 This example illustrates the trans- (lR, 2R) -2- (3,4-difluorophenyl) ring Preparation method of propanecarboxylic acid. Trans- (lR, 2R) -2- (3,4-difluorophenyl) cyclopropanone (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl ester (9.6 Kg, 91.8% non-mirror isomerically excessive) dissolved in ethanol (13.8 kg) and heated to 46 ° C with stirring. During 20 minutes, a 45% aqueous sodium hydroxide solution (3.1 kg) was added and the mixture was stirred for an additional 2 hours and 27 minutes. The solvent (28 liters) was distilled off from the mixture under reduced pressure, and then the mixture was cooled to 24 ° C and diluted with water (29.3 kg), and then the released methanol was extracted into toluene (3 times, each 3.3 kg) ). The residual aqueous phase was acidified to pH 2 with 37.0 / 0 hydrochloric acid (33 liters), and the product was extracted into toluene (8.6 kg and then two extractions of 4.2 kg and 4.3 kg). The combined toluene extract was washed with 1% hydrochloric acid (4.9 liters), then diluted with toluene (4.2 kg), and the solvent (25 liters) was distilled off under reduced pressure via i02725.doc -16- 200540149. . Diluted with dibenzyl (24.2 kg) and then distilled off the solvent (10 liters) under reduced pressure to obtain trans- (lR, 2R) -2- (3,4-difluorophenyl) cyclopropanesulfonic acid (about 3.45 Kg) solution, which is suitable for the preparation of trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropaneweiyl chloride. Example 10 This example illustrates a method for preparing trans- (111,211) -2- (3,4-difluorophenyl) cyclopropanecarbonyl chloride. _ Add pyridine (70 ml) to the trans_ (1r, 2r) _2- (3,4-: fluorophenyl) cyclopropanecarboxylic acid (about 3.45 kg) / toluene (about 12-15 kg) prepared above The solution was then heated to 65 ° C. Add sulfenyl chloride (2.3 kg) over 1 hour and stir the mixture at 7 (rC for 3 hours. Add sulfinylsulfur gas (0.5 kg) and place the mixture at 70 ° C and stir for 2 more Hour. Add the last portion of sulphur yellow gas (0.5 kg) and stir the reaction mixture at 70 ° C for 1 hour, then cool to 40 ° C. The solvent (about 60 liters) is distilled off under reduced pressure from the mixture. ), Toluene was periodically added (45 kg, 15 kg each three times). Then, trans- (lR, 2R) -2- (3,4-difluorophenyl) cyclopropanecarbonyl chloride was added. (About 3.8 kg) / toluene (about 6-9 liters) solution was cooled to 20 ° C. Example 11 This example illustrates the trans- (lR, 2R) -2_ (3,4_: fluorophenyl) ring Method for preparing propane carbonyl azide. A solution of trans_ (lR, 2R) -2- (3,4-difluorophenyl) cyclopropane carbonyl chloride (about 3.8 kg) / toluene (about 6-9 liters) in lt : Add to a mixture containing sodium azide (1.24 kg), tetrabutylammonium bromide (56 g) and sodium carbonate (922 g) in water (6.2 kg) over a period of 74 minutes. The mixture was placed at 102725.doc 17 200540149 Stir for 1 hour and 55 minutes, then dilute the water layer with cold water (3.8 kg), stir slightly, and separate. The toluene layer was washed once with water (3.8 kg) at 0 ° C, and then gasified with 20% Sodium aqueous solution (3.8 liters) was extracted and stored at 3t for subsequent use. Example 12 This example illustrates trans- (111,28) -2- (3,4-difluorophenyl) cyclopropylamine Preparation method: Refer to the cold trans- (lR, 2R) -2- (3,4-difluorophenyl) cyclopropane carbonyl azide solution prepared in Example 11 over a period of 41 minutes. Stir the toluene (6.0 kg). Stir the mixture for an additional 55 minutes at 100 ° C, then cool to 20 ° C, and add to 2 ° and 15 minutes to disperse at 80 ° C. In hydrochloric acid (3M, 18.2 kg). After 65 minutes, the solution was diluted with water (34 kg) and cooled to 25 ° C. The toluene layer was removed and the aqueous layer was basified with a 45% aqueous sodium hydroxide solution (3.8 kg). To pH 12. The product was then extracted into ethyl acetate (31 kg) and washed twice with water (13.7 kg each) to obtain the anti-_ii (1R, 2S) -2- (3,4-di Phenyl) cyclopropylamine (2.6 kg, 91.8% isomerically excess) in ethyl acetate (29.5 liters). Example 13 This example illustrates (2R) -2-hydroxy-2- Method for preparing trans- (lR, 2S) -2- (3,4-: fluorophenyl) cyclopropane ammonium phenylacetate. Mandelic acid (2.26 kg) is added to the product containing trans- (ir, 2S) -2 -(3,4-: Iphenyl) cyclopropylamine (2.6 kg, 91.8% isomerically excess) in an ethyl acetate (45.3 liter) solution stirred at 17 ° C. The mixture was stirred at 25 ° C for 3 hours and 8 minutes, then filtered and washed twice with ethyl acetate (102725.doc -18-200540149 1 3.8 kg). The crystalline product was dried under reduced pressure at 4 ° C for 23 hours to obtain (211) -2-hydroxy-2-phenylacetic acid trans- (111,28) -2- (3,4-difluorophenyl) cyclopropane Ammonium salt (4.45 kg).

m 102725.doc -19-

Claims (1)

200540149 • 10. Scope of patent application: 1. A formula (I), (la), (II), (III), (V), (Va), (VI), (Via), (VII), (Vila ), (VIII), (Villa), (IX) and (IXa) intermediate compounds. 2 · An intermediate compound, which is: trans_2- (3,4-difluorophenyl) cyclopropanecarboxylic acid (lR, 2S, 5R) -2-isopropyl-5 -methylcyclohexamidine Purpose; • trans- (lR, 2R) -2- (3,4-difluorophenyl) cyclopropanecarboxylic acid (lR, 2S, 5R) -2-isopropyl-5-methylcyclohexyl ester; ( E) -3- (3,4-difluorophenyl) -2-acrylic acid (lR, 2S, 5R) -2-isopropyl-5-fluorenylcyclohexyl ester; (E) -3- (3, 4-difluorophenyl) _2-acrylic acid; (E) -3- (3,4-difluorophenyl) -2-propenesulfonyl chloride; trans_ (lR, 2R) -2- (3,4-di Fluorophenyl) cyclopropanecarboxylic acid; trans- (lR, 2R) -2- (3,4-difluorophenyl) cyclopropanecarbonyl chloride; benzyl- (lR, 2R) -2- (3,4- Difluorophenyl) cyclopropanecarbonyl azide; trans- (lR, 2S) -2- (3,4-difluorophenyl) cyclopropylamine; and (211) -2-hydroxy-2-phenylacetic acid trans -(111,23) -2- (3,4-difluorophenyl;) cyclopropane ammonium salt. 102725.doc 200540149 VII. Designated representative maps ... (1) The designated representative maps in this case are: (none) (II) Brief description of the component symbols of this representative map: 8. If there is a chemical formula in this case, please disclose the features that best show the invention Chemical formula: (none) 102725 doc