Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines

Definitions

• the present invention relates to the technical field of the preparation of pharmaceutical intermediates, in particular, relates to a method for preparing 3-amino-N-cyclopropyl- 2-hydroxyl-hexanamide.
• the compound concerned in the present invention is 3-amino-N-cyclopropyl-2-hydroxyl- hexanamide, which is an intermediate for the preparation of pharmaceutical products, such as antiviral medicaments.
• the compound can be used to synthesize Telaprevir, a medicine for the treatment of hepatitis C.
• Patent application WO2005058821A discloses a preparation method as follows:
• the second step adopts lithium aluminum hydride as the reducing agent, which is expensive and difficult to handle under industrial production.
• the third step adopts cyclopropyl isocyanide, which is difficult to obtain and is thus not suitable for industrial production.
• Patent application WO2007109023 A discloses a preparation method as follows: OXONE®, Na 2 EDTA, NaHCQ 3
• the objective of the present invention is to provide a method for the preparation of 3-amino-N-cyclopropyl- 2-hydroxyl-hexanamide, wherein the reactive conditions should be mild, the materials should be readily available and easily handled, and the method should be suitable for industrial production.
• the present invention provides a method for the preparation of 3-amino-N-cyclopropyl- 2- hydroxyl-hexanamide.
• the present invention provides following aspects of the invention.
• a method for the preparation of 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide which comprises the following steps:
• trans-2-hexenoic acid or C1-C4 alkyl ester thereof is epoxidated and is optionally esterified to obtain 3-propylepoxyethane-2-carboxylic acid or C1-C4 alkyl ester thereof;
• said 3-propylepoxyethane-2-carboxylic acid or C1-C4 alkyl ester thereof is ring-opened by nitrile and is optionally esterified to form 3-amino-2-hydroxyl hexanoic acid or C1-C4 alkyl ester thereof;
• step (a) trans-2-hexenoic acid is epoxidated to obtain 3-propylepoxyethane-2-carboxylic acid, which is subsequently esterified to obtain
• step (b) 3-propylepoxyethane-2-carboxylic acid or C1-C4 alkyl ester thereof is reacted with nitrile to form intermediate 2-substituted- 4-propyl-4,5-dihydro-oxazole-5-carboxylic acid or C1-C4 alkyl ester thereof, and the oxazole ring of the intermediate is subsequently opened to form 3-amino-2-hydroxyl-hexanoic acid or C1-C4 alkyl ester thereof.
• step (b) 3-propylepoxyethane- 2-carboxylic acid C1-C4 alkyl ester is reacted with nitrile to form 2-substituted-4-propyl-
• step (c) 3-amino-2-hydroxyl- hexanoic acid C1-C4 alkyl ester is reacted with cyclopropylamine to form 3-amino-N-cyclo- propyl-2-hydroxyl-hexanamide.
• step (c) 3-amino-2-hydroxyl hexanoic acid-Ci-C4 alkyl ester is in the form of an acid addition salt, preferably hydrochloride.
• step (a) said epoxidation is accomplished by reacting with hydrogen peroxide in the presence of catalyst(s).
• catalyst(s) is selected from a group consisting of sodium tungstate, cetylpyridinium chloride, and 12-phosphotungstate.
• organic solvent(s) is selected from a group consisting of dichloromethane, dichloroethane, ethyl acetate, and toluene.
• Method of aspect 14 or 15, wherein, the molar ratio of said esterifying agent(s) and 3-propylepoxyethane-2-carboxylic acid is 1-1.2: 1.
• said oxazole intermediate- forming reaction is carried out by reacting with nitrile in the presence of catalyst(s).
• said catalyst(s) is selected from a group consisting of concentrated sulfuric acid, fuming sulfuric acid, boron trifluoride etherate, and boron trifluoride acetonitrile.
• step (c) said reaction with cyclopropylamine is carried out in an alcoholic solvent.
• step (c) said reaction with cyclopropylamine is carried out in an alcoholic solvent.
• the present invention has following advantages as compared with the prior art.
• the operations are uncomplicated, the reactive conditions are mild, and the reactions can be carried out with materials readily available at low price and having low toxicities.
• step 2 By using water as the solvent in the epoxidation reaction of step 1 , the present invention is more economic and clean as compared with the prior art techniques, which employ solvents such as ethanol or dichloromethane.
• the present invention uses trans-2-hexenoic acid as staring material, renders a total yield of >61% of the final product 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide, the purity of which can be as high as above 99.4%;
• the method of the present invention is suitable for industrial production because: the operations are simple and convenient; the materials are readily available; the yield is high; the purity of the product is good; the requirement of equipments is low.
• trans-2-hexenoic acid 3-propyl- epoxyethane-2-carboxylic acid, 3-propylepoxyethane-2-carboxylic acid methyl ester, 2-methyl-4-propyl-4,5-dihydro-oxazole-5-carboxylic acid methyl ester, 3-amino-2-hydroxyl hexanoic acid, 3-amino-2-hydroxyl hexanoic acid methyl ester, 3-amino-N-cyclopropyl- 2-hydroxyl-hexanamide— have the following formula (VII), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (I), respectively:
• the present invention provides a method for the preparation of 3-amino-N-cyclopropyl- 2-hydroxyl-hexanamide, which comprises following steps:
• trans-2-hexenoic acid or C1-C4 alkyl ester thereof is epoxidated and is optionally esterified to obtain 3-propylepoxyethane-2-carboxylic acid or C1-C4 alkyl ester thereof;
• said 3-propylepoxyethane-2-carboxylic acid or C1-C4 alkyl ester thereof is ring-opened by nitrile and is optionally esterified to form 3-amino-2-hydroxyl hexanoic acid or C1-C4 alkyl ester thereof;
• trans-2-hexenoic acid C1-C4 alkyl ester may be used directly as the starting material, but preferably, trans-2-hexenoic acid is used as the starting material.
• the product of step (a) may be 3-propylepoxyethane-2-carboxylic acid, or 3-propylepoxyethane-2-carboxylic acid C1-C4 alkyl ester, preferably being 3-propylepoxyethane-2-carboxylic acid methyl ester.
• trans-2-hexenoic acid is epoxidated in step (a) to obtain 3-propylepoxyethane-2-carboxylic acid, which is subsequently esterified to obtain 3-propylepoxyethane-2-carboxylic acid C1-C4 alkyl ester, preferably being methyl ester.
• trans-2-hexenoic acid C1-C4 alkyl ester is epoxidated in step (a) to obtain 3-propylepoxyethane-2-carboxylic acid C1-C4 alkyl ester.
• Trans-2-hexenoic acid may also be esterified in step (a) to obtain trans-2-hexenoic acid C1-C4 alkyl ester, which is subsequently epoxidated to obtain 3-propylepoxyethane-2-carboxylic acid C1-C4 alkyl ester.
• trans-2-hexenoic acid is epoxidated in step (a) to obtain 3 -propylepoxy ethane- 2-carboxylic acid, which is then optionally esterified to obtain 3-propylepoxyethane-2-carboxylic acid C1-C4 alkyl ester.
• C1-C4 alkyl refers to straight or branched alkyl groups comprising 1-4 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, preferably methyl or ethyl, and most preferably methyl.
• the epoxidation of step (a) is carried out by reacting with hydrogen peroxide in the presence of catalyst(s).
• said catalyst(s) is at least one of sodium tungstate, cetylpyridinium chloride, and 12-phosphotungstate.
• epoxidation of step (a) is carried out in an aqueous solution.
• pH of the reactive solution is adjusted to 5-6. Alkaline solution is used to adjust pH.
• Said alkaline solution may be any one or more of, for instance, ammonia water, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, potassium hydroxide solution, sodium phosphate solution, potassium phosphate solution, sodium bicarbonate solution, or potassium bicarbonate solution.
• the process of said step (a) is as follows: trans-2-hexenoic acid is dissolved in water; catalyst(s) is added; pH is adjusted to 5-6 by alkaline solution(s); hydrogen peroxide is added within 1-2 hours at room temperature; after addition, the reaction is allowed to continue for 5-6 hours at 50-60°C, as a result 3 -propylepoxy ethane-2-carboxylic acid is obtained.
• the molar ratio of said trans-2-hexenoic acid or C1-C4 alkyl ester thereof, catalyst(s), hydrogen peroxide is 1 :0.1-0.2: 2.0-2.5.
• said esterification of step (a) is carried out by reacting the acid of formula (II) with an esterifying agent.
• Said esterifying agent may be any conventional reagent, preferably those that can transform carboxylic acid to its lower alkyl ester under mild conditions, such as dimethyl carbonate and dimethyl sulfate.
• said esterification of step (a), especially when dimethyl sulfate is used as the esterifying agent is carried out in a mixture of water and organic solvent(s). For example, the acid of formula (II) is dissolved in water, then organic solvent(s) is added so as to dissolve the esterifying agent that is about to be added.
• Said organic solvent can be any conventional organic solvent that can properly dissolve the esterifying agent, such as dichloromethane, dichloroethane, ethyl acetate, or toluene.
• pH of the reactive solution is adjusted to 8-9.
• Alkaline solution is used to adjust pH.
• Said alkaline solution may be any one or more of, for instance, ammonia water, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, potassium hydroxide solution, sodium phosphate solution, potassium phosphate solution, sodium bicarbonate solution, or potassium bicarbonate solution.
• the process of said esterification is as follows: 3-propylepoxyethane-2-carboxylic acid is dissolved in water; pH of the solution is adjusted to 8-9 by alkaline solution; organic solvent(s) is added; the temperature is controlled at 20-30°C dimethyl sulfate is added and dimethyl sulfate is added; after the addition, the reaction continues under stirring for 6-8 hours to yield 3-propylepoxyethane- 2-carboxylic acid methyl ester as shown by formula (III).
• the molar ratio of said esterifying agent such as dimethyl sulfate and 3-propylepoxyethane-2-carboxylic acid is
• step (a) of the method according to the present invention is to use dimethyl carbonate as the esterifiying agent.
• the reaction is preferably carried out in a solvent such as 1 -methyl pyrrolidone and DMSO.
• the amount of the solvent can be about 2-10 times of the weight of the starting material 3-propylepoxyethane-
• dimethyl carbonate is used together with an alkali metal carbonate such as potassium carbonate.
• an alkali metal carbonate such as potassium carbonate.
• the molar ratio among the starting material, dimethyl carbonate and alkali metal carbonate (potassium carbonate) can be about 1 :1-3:1 -3.
• the desired product can be extracted from the reaction mixture with a solvent such as toluene, methylene chloride, methyl t-butyl ether, ethyl acetate etc. From low toxicity point of view, dimethyl cabonate and similar agents are preferably used as the esterifying agent.
• step (b) 3-propylepoxyethane-2-carboxylic acid or C1-C4 alkyl ester thereof is ring-opened by nitrile and is optionally esterified to form 3-amino-2-hydroxyl hexanoic acid or C1-C4 alkyl ester thereof.
• 3-propylepoxyethane-2-carboxylic acid or C1-C4 alkyl ester thereof is reacted with nitrile to form an oxazole intermediate, 2-substituted- 4-propyl-4,5-dihydro-oxazole-5-carboxylic acid or C1-C4 alkyl ester thereof; and the ring of the intermediate is opened to form 3-amino-2-hydroxyl hexanoic acid or C1-C4 alkyl ester thereof.
• 3-propylepoxyethane-2-carboxylic acid as shown by formula (II) is reacted with nitrile in step (b) to form 2-substituted-4-propyl-4,5-dihydro-oxazole-5-carboxylic acid; then the ring is opened to form 3-amino-2-hydroxyl hexanoic acid.
• an epoxide ester is used.
• 3-propylepoxyethane-2-carboxylic acid methyl ester as shown by formula (III) is reacted with nitrile to form 2-substituted-4-propyl-4,5-dihydro-oxazole-5-carboxylic acid C1-C4 alkyl ester (preferably being methyl ester); the ring is then opened to form
• said "nitrile” can be an aliphatic nitrile, aromatic nitrile, or arylaliphatic nitrile (an aliphatic nitrile with an aromatic substituent).
• the nitrile is an aliphatic nitrile comprising 2-5 (2, 3, 4, or 5) carbon atoms, an aromatic nitrile comprising 7-11 carbon atoms, or an arylaliphatic nitriles comprising 8-10 carbon atoms.
• Representative aliphatic nitriles are acetonitrile, propionitrile, butyronitrile, valeronitrile.
• a representative aromatic nitrile is benzonitrile.
• arylaliphatic nitriles are phenylacetonitrile, phenylpropionitrile, etc.
• the nitrile is preferably acetonitrile, propionitrile or benzonitrile, most preferably acetonitrile.
• said synthesis of the oxazole intermediate in step (b) is carried out in the presence of excessive amount of nitrile, such as acetonitrile.
• said synthesis of the oxazole intermediate in step (b) is carried out in the presence of catalyst(s).
• Said catalyst(s) may be, for example, concentrated sulfuric acid, fuming sulfuric acid, boron trifluoride etherate, and boron trifluoride acetonitrile, preferably boron trifluoride acetonitrile.
• the oxazole intermediate- forming reaction is as follows: 3-propylepoxyethane-
• 2- carboxylic acid or 3-propylepoxyethane-2-carboxylic acid methyl ester is dissolved in acetonitrile, the solution is cooled down to 0-5°C, catalyst is added, after addition, the solution is warmed up to room temperature (20-25°C) and is stirred for 3-4 hours to allow the reaction to occur and to yield 2-methyl-4-propyl-4,5-dihydro-oxazole-5-carboxylic acid or 2-methyl- 4-propyl-4,5-dihydro-oxazole-5-carboxylic acid methyl ester.
• the molar ratio of said nitrile, catalyst, and 3-propylepoxyethane-2-carboxylic acid or 3-propylepoxyethane-2-carboxylic acid C1-C4 alkyl ester is 5-10: 1-1.2: 1.
• the oxazole intermediate is ring-opened in the presence of an acid.
• the oxazole intermediate is ring-opened in an aqueous solution.
• Any proper acid can be used in said ring-opening reaction.
• the acid is one of those acids that can form stable acid addition salts with the ring-opening product, 3-amino-2-hydroxyl hexanoic acid or 3-amino-2-hydroxyl hexanoic acid ester.
• the acid is, for example, hydrochloric acid, sulfuric acid or phosphoric acid.
• the process of the ring-opening of the oxazole intermediate is preferably as follows: 2-methyl-4-propyl-4,5-dihydro-oxazole-5-carboxylic acid or 2-methyl-4-propyl-4,5-di hydro-oxazole-5-carboxylic acid methyl ester is dissolved in water; concentrated hydrochloric acid is added and the mixture is reacted under reflux for about 8-10 hours to yield
• the molar ratio of said oxazole intermediate, water, concentrate hydrochloric acid is 1 : 1.0-3.0: 1.0-3.0.
• the product of the ring-opening reaction of the oxazole intermediate is in the form of an acid addition salt, which can be used in the subsequent reaction(s).
• said product is 3-amino-2-hydroxyl hexanoic acid hydrochloride or 3-amino-2-hydroxyl hexanoic acid methyl ester hydrochloride.
• the product of the ring-opening of oxazole intermediate in the presence of acid is 3-amino-2-hydroxyl hexanoic acid or acid addition salt thereof, prior to step (c), the product is preferably esterified to form 3-amino-2-hydroxyl hexanoic acid C1-C4 alkyl ester or acid addition salt thereof.
• said esterification of step (b) may be carried out under the same reactive conditions as those of step (a).
• the esterification of step (b) is preferably carried out through a reaction with C1-C4 lower alcohols. Said reaction can be carried in excessive amount of lower alcohols. Said reaction is preferably carried out in the presence of catalyst.
• catalyst is, for example, thionyl chloride, concentrated sulfuric acid, gaseous hydrogen chloride etc.
• the molar ratio of lower alcohols, thionyl chloride, and 3-amino-2-hydroxyl hexanoic acid or acid addition salt thereof is 8-10: 1-1.5: 1.
• the product of the esterification in step (b) is in an acid addition salt form with the same acid part as in the staring material.
• 3-amino-2-hydroxyl hexanoic acid or C1-C4 alkyl ester thereof in step (c) is reacted with cyclopropylamine to form 3-amino-N-cyclo- propyl-2-hydroxyl-hexanamide.
• 3-amino-2-hydroxyl hexanoic acid or acid addition salt thereof in step (c) is amidated to form 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide.
• 3-amino-2-hydroxyl hexanoic acid C1-C4 alkyl ester or acid addition salt thereof in step (c) is amidated to form 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide.
• said amidation of step (c) may be carried out in an alcoholic solvent, such as methanol, ethanol, or isopropanol.
• an alcoholic solvent such as methanol, ethanol, or isopropanol.
• the reaction can be carried out as follows: 3-amino-2-hydroxyl hexanoic acid methyl ester hydrochloride is dissolved in alcoholic solvent; cyclopropylamine is added within 1-2 hours at room temperature; after addition, the reaction is allowed to continue for 5-10 hours to yield 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide.
• the molar ratio of said 3-amino-2-hydroxyl hexanoic acid C1-C4 alkyl ester or acid addition salt thereof and cyclopropylamine is: 1 : 2-5.
• step (c) it is particularly beneficial to use reactant in its acid addition salt form, because it has been found to significantly prevent side reactions, and to ensure, without employing protection groups, high yield of the final product, 3-amino-N-cyclopropyl-2-hydroxyl- hexanamide.
• the present invention employs 3-amino-2-hydroxyl hexanoic acid methyl ester hydrochloride to react with cyclopropylamine, and yields 3-amino-N-cyclopropyl- 2-hydroxyl-hexanamide at a yield rate as high as 84%.
• the acid partner is preferably the same as the acid that is used in the ring-opening reaction of the oxazole intermediate in step (b).
• said acid addition salts can also be formed by reacting an acid with free 3-amino-2-hydroxyl hexanoic acid or C1-C4 alkyl ester thereof.
• the present invention provides a method for preparing 3-amino-N-cyclo- propyl-2-hydroxyl-hexanamide, which comprises following steps:
• trans-2-hexenoic acid is epoxidated to obtain 3-propylepoxyethane-2-carboxylic acid
• step (1) trans-2-hexenoic acid is dissolved in water and is reacted with hydrogen peroxide in the presence of catalyst. pH of the reaction solution is adjusted to 5-6 by alkaline solution. At room temperature, hydrogen peroxide is added within 1-2 hours. After addition, the reaction is allowed to continue for 5-6 hours at 50-60°C. After the reaction is completed, the reaction mixture is separated properly to yield 3-propylepoxyethane-2-carboxylic acid. The reaction mixture can instead be concentrated and directly used in the subsequent reaction without further separation.
• the alkaline solution can be any one or more of ammonia water, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, potassium hydroxide solution, sodium bicarbonate solution, or potassium bicarbonate solution, preferably sodium carbonate solution.
• step (1) the molar ratio of said trans-2-hexenoic acid, catalyst, hydrogen peroxide is 1 : 0.1-0.2: 2.0-2.5.
• said catalyst can be at least one of sodium tungstate, cetylpyridinium chloride, and 12-phosphotungstate, preferably cetylpyridinium chloride .
• step (2) the esterification is carried out as follows: 3-propylepoxyethane-2-carboxylic acid is dissolved in water; pH of the solution is adjusted to 8-9 by alkaline solution; organic solvent(s) is added; the temperature is controlled at 20-30°C and dimethyl sulfate is added. After addition, the reaction mixture is further reacted for 6-8 hours under stirring. After the reaction is completed, the reaction mixture is separated properly to yield 3-propylepoxyethane-2-carboxylic acid methyl ester as shown by formula (III). The reaction mixture can instead be concentrated and directly used in the subsequent reaction without further separation.
• the molar ratio of dimethyl sulfate and 3-propylepoxyethane-2-carboxylic acid is 1-1.2: 1.
• the solvent in step (2) can be any one of ethyl acetate, dichloromethane, dichloroethane, and toluene.
• the mass ratio of said solvent and 3-propylepoxyethane-2-carboxylic acid is 3.0-10.0: 1, preferably 3.0-5.0: 1, most preferably 5.0: 1.
• the alkaline solution can be at least one of ammonia water, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, potassium hydroxide solution, sodium bicarbonate solution, or potassium bicarbonate solution, preferably sodium carbonate solution.
• step (3) said synthesis of the oxazole intermediate is as follows: 3-propylepoxyethane-2-carboxylic acid methyl ester is dissolved in acetonitrile; the solution is cooled down to 0-5°C; the catalyst is added. After the addition, the reaction mixture is warmed up to room temperature and is reacted for 3-4 hours under stirring. After the reaction is completed, the reaction mixture is separated to yield 2-methyl-4-propyl-4,5-dihydro- oxazole-5-carboxylic acid methyl ester. Alternatively, the intermediate needs not be separated, and the reaction mixture can instead be concentrated and directly used in the subsequent reaction.
• said catalyst in step (3) is at least one of concentrated sulfuric acid, fuming sulfuric acid, boron trifluoride etherate, and boron trifluoride acetonitrile.
• said separation step may comprise: adjusting the pH of the reaction mixture to 5-6 with an alkaline solution to obtain an organic phase and an aqueous phase.
• the aqueous phase is extracted with dichloromethane.
• the dichloromethane extract and the organic phase are combined and concentrated under reduced pressure to yield
• the alkaline solution can be at least one of ammonia water, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, potassium hydroxide solution, sodium bicarbonate solution, and potassium bicarbonate solution, preferably sodium carbonate solution.
• step (4) the process of the ring-opening of the oxazole intermediate is, for instance, as follows: 2-methyl-4-propyl-4,5-dihydro-oxazole-5-carboxylic acid methyl ester is dissolved in water; concentrated hydrochloric acid is added and the reaction is conducted for 8-10 hours under stirring. After the reaction is completed, the reaction mixture is separated to yield
• reaction solution can alternatively be concentrated and directly used in the subsequent reaction without further purification.
• the molar ratio of 2-methyl-4-propyl-4,5-dihydro-oxazole-5-carboxylic acid methyl ester, water, concentrated hydrochloric acid is 1 : 1.0-3.0: 1.0-3.0.
• step (5) the esterification of 3-amino-2-hydroxyl hexanoic acid hydrochloride is, for instance, as follows: 3-amino-2-hydroxyl hexanoic acid hydrochloride is dissolved in methanol; the solution is cooled down to 0-5°C and thionyl chloride is added. After the addition, the reaction is allowed to continue for 20-25 hours at room temperature. Upon separation, 3-amino-2-hydroxyl hexanoic acid methyl ester-hydrochloride is then obtained. The reaction mixture can alternatively be concentrated and directly used in the subsequent reaction without further purification.
• the molar ratio of methanol, thionyl chloride, 3-amino-2-hydroxyl hexanoic acid-hydrochloride is 8-10: 1-1.5: 1.
• step (6) the amidation can be carried out as follows: 3-amino-2-hydroxyl hexanoic acid methyl ester hydrochloride is dissolved in an alcoholic solvent; cyclopropylamine is added within 1-2 hours at room temperature. After addition, the reaction is allowed to continue for 5-10 hours. 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide is separated. The molar ratio of said 3-amino-2-hydroxyl hexanoic acid methyl ester hydrochloride and cyclopropylamine is 1 : 2-5.
• said alcoholic solvent in step (6) is at least one of methanol, ethanol, or isopropanol. The weight of the added alcohol is 2-5 times to that of the added 3-amino-2-hydroxyl hexanoic acid methyl ester hydrochloride.
• the separation in step (6) is preferably as follows: the solution is concentration under reduced pressure to remove the solvent; pH of the solution is adjusted to 11-13 by alkaline solution; the solution is then extracted by extracting solvent; the resulted extraction phase is concentrated to yield the crude product— free 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide as shown by formula (I).
• the crude product is further re-crystallized to yield 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide with high purity.
• the extracting solvent is preferably at least one of dichloromethane, butanol or isopropanol.
• the weight of the added extracting solvent is 10-50 times to that of 3-amino-2-hydroxyl hexanoic acid methyl ester hydrochloride.
• the solvent used for re-crystallization is at least one of methanol, ethanol, isopropanol, or acetonitrile.
• the weight of the added re-crystallizing solvent is 1-5 times to that of the crude 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide.
• the alkaline solution can be at least one of ammonia water, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, potassium hydroxide solution, sodium bicarbonate solution, or potassium bicarbonate solution, preferably sodium carbonate solution.
• the weight of water to be added in step (1) and (2) is 3-10 times to that of trans-2-hexenoic acid.
• the present invention relates to the following aspects.
• a method for the preparation of 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide which comprises the following steps:
• trans-2-hexenoic acid as shown in formula (VII) is dissolved in water, the catalyst is added, pH of the reaction solution is adjusted to 5-6 by alkaline solution; at room temperature, hydrogen peroxide is added dropwise within 1-2 hours; after addition, the reaction is allowed to continue for 5-6 hours at 50-60°C; after the reaction is completed, the pH of the reaction mixture is adjusted to 1 -2 by concentrated hydrochloric acid; the reaction mixture is extracted by dichloromethane and the organic phase is concentrated to dryness, 3-propylepoxy- ethane-2-carboxylic acid as shown in formula (II) is then obtained;
• step 1) 3-propylepoxyethane-2-carboxylic acid obtained in step 1) is dissolved in water; pH of the solution is adjusted to 8-9 by alkaline solution; organic solvent is added; the temperature is controlled at 20-30°C and dimethyl sulfate is added dropwise; after addition, the reaction mixture is further reacted for 6-8 hours under stirring; after the reaction is completed, the reaction mixture is layered by standing by, the organic phase is concentrated under reduced pressure, then 3-propylepoxyethane-2-carboxylic acid methyl ester of formula (III) is obtained, wherein the molar ratio of dimethyl sulfate to 3-propylepoxyethane-2-carboxylic acid is 1-1.2:1 ; 4) 3-propylepoxyethane-2-carboxylic acid methyl ester (formula III) obtained in step 3) is dissolved in acetonitrile; the solution is cooled down to 0-5°C; the catalyst is added dropwise; after the addition, the reaction mixture is war
• step 5 3-amino-2-hydroxyl hexanoic acid hydrochloride obtained in step 5) is dissolved in methanol; the solution is cooled down to 0-5°C and thionyl chloride is added dropwise; after the addition, the reaction is allowed to continue for 20-25 hours at room temperature; the reaction mixture is concentrated under reduced pressure and 3-amino-2-hydroxyl hexanoic acid methyl ester-hydrochloride of formula (VI) is then obtained, wherein the molar ratio of methanol, thionyl chloride, 3-amino-2-hydroxyl hexanoic acid-hydrochloride is 8-10: 1-1.5: 1 ;
• step (6) 3-amino-2-hydroxyl hexanoic acid methyl ester hydrochloride obtained in step (6) is dissolved in a solvent alcohol; cyclopropylamine is added dropwise within 1-2 hours at room temperature; after addition, the reaction is allowed to continue for 5-10 hours until the full consumption of the raw materials; the solvents are removed by concentration under reduced pressure, pH of the mixture is adjusted to 11-13 by alkaline solution and the mixture is extracted by extracting solvents; the resulted extraction phase is concentrated to yield the crude product of free 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide as shown in formula (I); the crude product is further re-crystallized to yield 3-amino-N-cyclopropyl-2-hydroxyl- hexanamide with high purity, wherein the molar ratio of said 3-amino-2-hydroxyl hexanoic acid methyl ester hydrochloride to cyclopropylamine is 1 : 2-5.
• the alkaline solution of step 2), step 3), step 4) and step 7) is any one selected from the group consisted of ammonia water, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, potassium hydroxide solution, sodium phosphate solution, potassium phosphate solution, sodium bicarbonate solution and potassium bicarbonate solution.
• the molar ratio of trans-2-hexenoic acid, catalyst and hydrogen peroxide is 1 :0.1-0.2:2.0-2.5.
• the catalyst in one selected from a group consisting of sodium tungstate, cetylpyridinium chloride, and 12-phosphotungstate.
• step 2) the mass of water added in step 2) and step 3) is 3-10 times of the mass of trans-2-hexenoic acid.
• the organic solvent of step 3 is any one selected from the group consisting of ethyl acetate, dichloromethane, dichloroethane and toluene; the mass ratio of the solvent(s) to 3-propylepoxyethane-2-carboxylic acid is 3.0-10.0: 1, preferably 3.0-5.0: 1 and most preferably 5.0: 1.
• the catalyst of step 4) is any one selected from the group consisting of concentrated sulfuric acid, fuming sulfuric acid, boron trifluoride etherate, and boron trifluoride acetonitrile.
• the solvent alcohol of step 7) is any one selected from the group consisting of methanol, ethanol, and isopropyl alcohol, wherein the mass is 2-5 times of mass of 3-amino-2-hydroxyl hexanoic acid methyl ester hydrochloride.
• the extracting solvent of step 7) is any one selected from the group consisting of dichloromethane, n-butyl alcohol and isobutyl alcohol, wherein the mass is 10-50 times of mass of 3-amino-2-hydroxyl hexanoic acid methyl ester hydrochloride.
• the re-crystallization solvent(s) of step 7) is any one selected from the group consisting of methanol, ethanol, isobutyl alcohol and acetonitrile, wherein the mass is 1 -5 times of mass of 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide crude product.
• Example 1 To a 1L reaction flask, 400g water was added, and then trans-2-hexenoic acid (45.7g, 0.4mol) and cetylpyridinium chloride (13.6g, 0.04mol) were added under stirring. The pH of the solution is adjusted to 6 with 30% sodium hydroxide solution. 30% aqueous solution of hydrogen peroxide (91g, 0.8mol) was added at room temperature. Then the reaction mixture was heated to 50°C and allowed to react for 6 hours until completion. The reaction mixture was collected to room temperature and the pH was adjusted to 2 with concentrated hydrochloric acid. The mixture was extracted twice with 400g dichloromethane. The extract was concentrated until dryness. 48.6g 3-propylepoxyethane-2-carboxylic acid was obtained with a yield of 92%. The molecular weight of the compound was confirmed by GC-MS.
• the same technical effect can be rendered if one replaces sodium hydroxide solution with ammonia water, sodium carbonate solution, potassium carbonate solution, potassium hydroxide solution, sodium bicarbonate solution, or potassium bicarbonate solution, and/or replaces cetylpyridinium chloride with sodium tungstate or 12-phosphotungstate.
• Example 2 To a 1L reaction flask, 130g water was added and then trans-2-hexenoic acid (45.7g, 0.4mol) and sodium tungstate (26.4g, 0.08mol) were added under stirring. The pH of the mixture was adjusted to about 5 with sodium carbonate solution. 30% aqueous solution of hydrogen peroxide (91g, 0.8mol) was added into the reaction mixture at room temperature. The reaction mixtures was then heated to 60°C and was allowed to further react for about 5 hours until completion of the reaction. The reaction mixture was cooled to room temperature and the pH was adjusted to about 1 with concentrated hydrochloric acid. The mixture was extracted twice with 400g dichloromethane. The extract was concentrated until dryness.
• Example 4 To a 1L reaction flask, 530g water was added and 3-propylepoxy- ethane-2-carboxylic acid (53g, 0.4mol) was added under stirring. The pH of the mixture was adjusted to about 8.5 with 30% sodium hydroxide solution and 265g dichloromethane was added into the mixture. Me 2 S0 4 (60.5g, 0.48mol) was then added dropwise at 25°C. The dropwise addition lasted for about 1 hour. Afterward, the reaction was allowed to continue for 6 hours The reaction mixture was allowed to stand until it was separated into two layers. The organic phase was separated, dried with MgS0 4 and then concentrated until dryness. 50.3g 3-propylepoxyethane-2-carboxylic acid methyl ester was obtained with a yield of 88.3%. The molecular weight of the compound was confirmed by GC-MS.
• the same technical effect can be rendered if one replaces sodium hydroxide solution with ammonia water, sodium carbonate solution, potassium carbonate solution, potassium hydroxide solution, sodium bicarbonate solution, or potassium bicarbonate solution, and/or replaces dichloromethane with any one of ethyl acetate, dichloroethane, and toluene, with any mass ratio of the solvent and 3-propylepoxyethane-2-carboxylic acid from 3.0: 1 to 10.0: 1.
• Example 5 To a 1L reaction flask, 155g water was added and then 3-propylepoxy- ethane-2-carboxylic acid (formula II) (53g, 0.4mol) was added under stirring. The pH of the mixture was adjusted to about 9 with 10% Na 2 C0 3 aqueous solution. 530g toluene and 5.3g benzyltrimethylammonium chloride were then added into the mixture. Me 2 S0 4 (50. Og, 0.4mol) was added dropwise at 20°C for about 1 hour. Afterward, the reaction was allowed to continue for about 8 hours until the completion. The reaction mixture was allowed to stand until it was separated into two layers. The organic phase was separated, dried with MgS0 4 and then concentrated until dryness.
• formula II 3-propylepoxy- ethane-2-carboxylic acid
• Example 7 To a 1L reaction flask, 155g water was added, under stirring, 3-propylepoxy- ethane-2-carboxylic acid (formula II) (53g, 0.4mol) was then added. The pH was adjusted to 9 with 10% sodium carbonate solution. 370g dichloromethane was added and dimethyl sulfate (Me 2 S0 4 , 55. Og, 0.44mol) was added dropwise at 20°C and the adding time was about 1 hour. Afterwards, the reaction was allowed to continue for 7 hours until completion of the reaction. Standing by and layering, the organic layer was dried with magnesium sulfate and concentrated to dryness. 51.3g product was obtained with a yield of 90%>.
• Example 8 To a 5L reaction flask, 3-propylepoxyethane-2-carboxylic acid methyl ester (288g, 2.0mol) and CH 3 CN (820g, 20mol) were added. When the reaction mixture was cooled to 0°C in ice bath, boron trifluoride acetonitrile (240g, 2.2mol) was added dropwise for about 1 hour. Afterward, the reaction mixture was warmed up to room temperature. The reaction was allowed to continue for another 3-4 hours until the completion. The pH of the reaction mixture was adjusted to about 5 with 5% sodium bicarbonate solution. The mixture was allowed to stand until it was separated into two layers. The aqueous layer was separated and extracted twice with 2500g dichloromethane.
• Example 9 To a 5L reaction flask, 3-propylepoxyethane-2-carboxylic acid methyl ester (288g, 2.0mol) and CH 3 CN (410g, l Omol) were added. When the reaction mixture was cooled to 5°C in ice bath, concentrated sulfuric acid (196g, 2.0mol) was added dropwise for about 1 hour. Afterward, the reaction mixture was warmed up to room temperature 25°C. The reaction was allowed to continue for another 4 hours until completion. The pH of the reaction mixture was adjusted to about 6 with 10% sodium hydroxide solution. The mixture was allowed to stand until it was separated into two layers. The aqueous layer was separated, extracted twice with 1500g dichloromethane. The extracts were combined with the organic layer and were concentrated under reduced pressure.
• 3-propylepoxyethane-2-carboxylic acid methyl ester 288g, 2.0mol
• CH 3 CN 410g, l Omol
• Example 10 To a 5L reaction flask, 3- propylepoxyethane-2-carboxylic acid methyl ester (288g, 2.0mol) and acetonitrile (410g, lOmol) were added. When the reaction mixture was cooled to 5°C by ice bath, boron trifluoride acetonitrile (240g, 2.2 mol) was added dropwise and the adding time was about 1 hour. Afterwards, the temperature increased to room temperature of 25°C and the reaction was allowed to continue for 4 hours until completion of the reaction. The pH was adjusted to 6 with 10%> sodium hydroxide. After standing by and layer-separation, the water layer was extracted twice with 1500g dichloromethane. The organic layers were combined and concentrated under reduced pressure. 347.5g product was obtained with a yield of 94%.
• Example 11 To a 2L reaction flask, 2-methyl-4-propyl-4,5-dihydro-oxazole-5-carboxylic acid methyl ester (formula IV) (370g, 2.0mol), 740g water and 740g concentrated hydrochloric acid were added. The reaction mixture was heated to reflux for about 10 hours. The aqueous layer was concentrated until dryness. 370g (99% purity) of 3-amino-2-hydroxyl hexanoic acid hydrochloride was obtained with a yield of 100%).
• Example 12 To a 2L reaction flask, 2-methyl-4-propyl-4,5-dihydro-oxazole-5-carboxylic acid methyl ester (formula IV) (370g, 2.0mol), l l lOg water and l l lOg concentrated hydrochloric acid were added. The reaction mixture was heated to reflux for about 8 hours. The aqueous layer was concentrated until dryness. 370g (99% purity) of 3-amino-2-hydroxyl hexanoic acid-hydrochloride was obtained with a yield of 100%>.
• Example 13 To a 2L reaction flask, 3-amino-2-hydroxyl hexanoic acid-hydrochloride (formula V) (367g, 2.0mol) and methanol (640g, 20mol) were added. The reaction mixture was cooled to 0-5°C and thionyl chloride (248.5g, 2.2mol) was added dropwise. After the addition, the reaction was allowed to continue for 20-25 hours at room temperature. The reaction mixture was then concentrated until dryness. 360g 3-amino-2-hydroxyl hexanoic acid methyl ester-hydrochloride was obtained with a yield of 95%.
• 3-amino-2-hydroxyl hexanoic acid methyl ester-hydrochloride was obtained with a yield of 95%.
• Example 14 To a 2L reaction flask, methanol (640g, 20mol) was added and cooled to 0-5°C. After introducing gaseous hydrogen chloride (176g, 4.8mol) into the methanol, 3-amino-2-hydroxyl hexanoic acid-hydrochloride (formula V) (367g, 2.0mol) was added. The reaction was allowed to continue for 20-25 hours at room temperature. The reaction mixture was then concentrated until dryness. 345g 3-amino-2-hydroxyl hexanoic acid methyl ester-hydrochloride was obtained with a yield of 92%.
• Example 15 To a 2L flask, the above mentioned 3-amino-2-hydroxy-hexanoic acid hydrochloride (formula V) (370g, 2.0mol) and methanol (512g, 16mol) were added. The mixture was cooled to 5°C and thionyl chloride (338.9g, 3mol) was added dropwise. Afterwards, the reaction was allowed to continue for 20 hours at room temperature. Then the reaction mixture was concentrated to dryness and 296.8g product was obtained with a yield of 94%.
• Formula V 3-amino-2-hydroxy-hexanoic acid hydrochloride
• methanol 512g, 16mol
• Example 17 To a 2000ml flask, 840g isopropanol and cyclopropylamine (245g, 4.3mol) were added. The reaction mixture was cooled to 20°C and 3-amino-2-hydroxyl hexanoic acid methyl ester hydrochloride (formula VI) (280g, 1.42mol) was added under stirring. After 30min, a large amount of solid precipitated. Thereafter, the mixture was stirred overnight at room temperature. Then the reaction mixture was filtered. The precipitated solid was dried and 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide-hydrochloride (281.8g, crude yield of 89.1%) was obtained.
• 3-amino-2-hydroxyl hexanoic acid methyl ester hydrochloride (formula VI)
• the same technical effect can be rendered if one replaces isopropanol with methanol or ethanol as the alcoholic solvent while the weight of the alcoholic solvent is 2-5 times of that of the added 3-amino-2-hydroxyl hexanoic acid methyl ester-hydrochloride, and/or replaces dichloromethane with either one ofbutanol or isopropanol as the extracting agent while the weight of the extracting agent is 10-50 times of that of
• Example 18 To a 2000ml four-necked flask 560g methanol and cyclopropylamine (323.8g, 5.68mol) were added. The reaction mixture was cooled to 10-20°C and 3-amino-2-hydroxyl hexanoic acid methyl ester hydrochloride (formula VI) (280g, 1.42mol) was added under stirring. After 30min, a large amount of solid precipitated. Thereafter, the mixture was stirred overnight at room temperature. Then the reaction mixture was filtered and the precipitated solid was dried to give 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide-hydrochloride (290g, crude yield of 91.6%).
• 3-amino-2-hydroxyl hexanoic acid methyl ester hydrochloride (formula VI)
• the resulted product was tested and was verified to be 3-amino-N-cyclopropyl- 2-hydroxyl-hexanamide.
• the 'HNMR data obtained are set forth as follows: 'H-NMR (d-DMSO, 400Hz): ⁇ .46 (cyclopropyl CH 2 , m), ⁇ .59 (cyclopropyl CH 2 , m), ⁇ .82 (CH 3 , t), ⁇ .11-1.43 (CH 2 , m), ⁇ 2.64 (cyclopropyl CH, m), ⁇ 2.8 (amino-linked CH, m), 53.86 (hydroxyl-linked CH, d), ⁇ 7.70 (NH, d).

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