HK1020281A

HK1020281A - NOVEL ASYMMETRIC SYNTHESIS OF R-α-PROPYL-PIPERONYL AMINE AND ITS ANALOGUES

Info

Publication number: HK1020281A
Application number: HK99105431.8A
Authority: HK
Inventors: H-Y‧李; L‧安扎罗纳; R‧E‧瓦尔特米雷
Original assignee: 杜邦药品公司
Priority date: 1996-03-22
Filing date: 1997-03-17
Publication date: 2000-04-07

Description

Novel method for asymmetric synthesis of R-alpha-propyl-piperonyl amine and analogues thereof

Technical Field

The present invention relates to processes for the preparation of R- α -propyl-piperonylamine and analogs thereof, which are useful intermediates for the preparation of elastase inhibitors, and to intermediates useful in the preparation of R- α -propyl-piperonylamine.

Background

[ S- (R) represented by the following formula^*,S^*]N- {1- (1, 3-benzodioxol-5-yl) butyl]-3, 3-diethyl-2- [4- [ (4-methyl-1-piperazinyl) carbonyl]Phenoxy radical]-4-oxo-1-azetidinecarboxamide (EI):

is a non-toxic selective elastase inhibitor with oral activity, and is widely used for treating pancreatic fibrosis. Therefore, a large amount of (EI) is required to support drug development studies.

Synthetic routes to analogous (EI) compounds have been described, for example, in EP 0,481,671. This document suggests that (EI) may be formed by linking a substituted lactam moiety of (EI) with R- α -propyl-piperonyl via a carbonyl linker. Thus, the chiral amine R- α -propyl-piperonyl amine becomes an important intermediate in this process if an efficient industrial scale production route is known.

Humphrey et al, in U.S. Pat. No. 5,149,838, describe the formation of (R) -1- (benzo [ B ] furan-5-yl) -1-aminobutane from 5-bromobenzo [ beta ] furan. The last step of the process involves the conversion of (S) -1- (benzo [ β ] furan-5-yl) -1-butanol under Mitsonobu conditions to form (R) -1- (benzo [ β ] furan-5-yl) -1-aminobutane. Unfortunately, when the Mitsunobu method is applied to the synthesis of R-or S- α -propyl-piperonylamine (i.e. an intermediate for the preparation of compounds like EI), side reactions and loss of stereochemistry become major problems.

Bringmann et al describe in DE 3,819,438 a process for the formation of chiral amines by the following reaction: reacting a substituted aryl ketone with chiral methylbenzylamine, hydrogenating the resulting imine with Ra-Ni at 1-200bar and 20-60 ℃ and then removing the phenethyl group by hydrogenation in the presence of Pd/C at 1-200bar and 20-50 ℃. Bringmann et al in tetrahedron letters (Tetr. Lett.),1989,30(3),317 report a reaction for the hydroreduction of a chiral imine formed from S- α -methylbenzylamine in ethanol in the presence of Ra-Ni at a hydrogen pressure of 5 bar. Bringmann et al also reported in the Synlett (Synlett)1990,253 at a pressure of 60bar with the aid of Pd/C or NaBH₄Hydrogenation reduction of a chiral imine formed from S- α -methylbenzylamine. In addition, Bringmann et al also describe in detail in Leibigs ann. chem.1990,795 the hydrogenolysis of N- (1-phenylethyl) -1-arylethylamine using hydrogen with palladium-on-carbon for three weeks, or the hydrogenolysis of the above compounds using ammonium formate with palladium-on-carbon. However, the present inventors have found that hydrogenolysis of (R) -N- [1- (1, 3-benzodioxol-5-yl) butylene by the method described by Bringmann et al]Alpha-methylbenzylamine is either very slow in the reaction or racemization of R-alpha-propyl-piperonyl amine occurs.

The hydrogenation of chiral amines, in particular N- (methyl (o-methoxy) benzylidene) - α -methylbenzylamine, is reported by Eleveld et al in journal of organic chemistry (J.org.chem.)1986,51, 3635. Hydrogenation with Pd/C and 3atm hydrogen pressure can produce greater than 90% de SS isomer. In contrast, the corresponding m-methoxyimine gives only 67% de. The reason for the high de values obtained with o-methoxy compounds is due to the steric hindrance of the o-methoxy group. It is readily recognized that R-and S- α -propyl-piperonyl amine contain only m-methoxy groups. Thus, the process of Eleveld et al cannot be used to prepare R-and S- α -propyl-piperonylamine.

Ukaji et al, in chemical communication (chem. Lett.)1991,173, indicate that the reaction of oxime ethers with allyl magnesium bromide is very diastereoselective. If the oxime ether is separated into the E and Z isomers, allylmagnesium bromide complexed with cerium chloride provides 50-72% de. Based on this report, cerium chloride may be required for the reaction if a grignard reaction is used as an intermediate step in the formation of R-or S- α -propyl-piperonylamine. However, cerium chloride is generally prohibited and 50-72% de is too low.

Wu et al, journal of organic chemistry (J.org.chem.)1991,56,1340 report the diastereoselective addition of Grignard reagents such as methyl, ethyl and butyl to 2-aryl-1, 3-oxazolidines. Furthermore, it is indicated that cerium trichloride increases the diastereoselectivity of the Grignard addition reaction. The addition reaction of methyl magnesium bromide and p-methoxyphenyl-4-phenyl-1, 3-oxazolidine can obtain high diastereoselectivity, but the yield is only 45%. Such low yields are clearly unsuitable for industrial purposes.

Higashiyama et al discuss the Grignard addition reaction to chiral aliphatic imines derived from (R) -O-methylphenylglycerol in the Chemicals newspaper (chem. pharm. Bull.)1995,43(5), 722. But cerium trichloride was used. Wherein the removal of phenylglycinol is accomplished by hydrogenation in ethyl acetate in the presence of palladium hydroxide.

From the above documents, it can be seen that it is difficult to efficiently mass-produce R-and S- α -propyl-piperonylamine without using a poor reagent. Therefore, it is desirable to find a new synthetic method that can produce R- α -propyl-piperonyl amine and its analogs on an industrial scale.

Summary of The Invention

It is therefore an object of the present invention to provide a novel process for the preparation of a compound of formula i:

it is a further object of the present invention to provide novel compounds of formulae IV and VII as defined below which are useful intermediates for the preparation of compounds of formula I.

These and other objects of the present invention will become apparent from the following detailed description, and all of these objects can be achieved by the inventors' discovery that a compound of formula i, or a stereoisomer or salt form thereof, can be formed in high yield by a highly regioselective process comprising:

(a) reacting a compound of formula II:

with chiral methylbenzylamine to form a compound of formula iii:wherein R is selected from H, OH and OCH₃；

(b) Hydrogenating a compound of formula iii, or a stereoisomer or salt form thereof, in the presence of Ra-Ni to form a compound of formula iv, or a diastereomer or salt form thereof:

wherein the hydrogenation reaction is carried out under conditions selected from the group consisting of:

(ii) a hydrogen pressure of about 0.01-3000psi and a temperature; or

(bii) a hydrogen pressure of about 0.01-3000psi and a first temperature and a second temperature greater than the first temperature; and the combination of (a) and (b),

(c) hydrogenating a compound of formula iv or a stereoisomer or salt form thereof to form a compound of formula i or a stereoisomer or salt form thereof; or

(d) Reacting a compound of formula v:

(ii) with chiral methylbenzylamine to form a compound of formula vi:

wherein R is H, OH or OCH₃；

(e) Contacting a compound of formula vi, or a stereoisomer or salt form thereof, with allylmagnesium bromide to form a compound of formula vii, or a diastereomer or salt form thereof:wherein R is H, OH or OCH₃(ii) a And

(f) hydrogenating the compound of formula VII or a diastereoisomeric or salt form thereof in the presence of palladium-on-carbon to form the compound of formula I or a stereoisomer or salt form thereof.

Detailed Description

[1]Accordingly, in a first embodiment, the present invention provides a method of synthesizing a compound of formula i:

the method comprises the following steps:

(a) reacting a compound of formula II:

with chiral methylbenzylamine to form a compound of formula iii:

wherein R is selected from H, OH and OCH₃；

(ii) at a temperature of from 0 ℃ to 100 ℃ for from about 2 hours to about 30 hours under a hydrogen pressure of from about 0.01 psi to about 10 psi, or at a temperature of from 60 ℃ to about 80 ℃ for from about 2 hours to about 30 hours under a hydrogen pressure of from 10 psi to about 3000 psi; or

(bii) at about 0.01 to 3000psi of hydrogen pressure, at a first temperature of 0 to 35 ℃ for about 2 to 8 hours, and at a second temperature of 50 to 100 ℃ for about 2 to 24 hours; and

(c) hydrogenating a compound of formula iv or a stereoisomer or salt form thereof in the presence of palladium-on-carbon and a solvent selected from the group consisting of alcohols, carboxylic acids, dicarboxylic acids, aromatic carboxylic acids, and mixtures thereof to form a compound of formula i or a stereoisomer or salt form thereof;

with the proviso that the compound of formula IV hydrogenated in step c cannot be a hydrobromide salt.

[2]In a preferred embodiment, the chiral methylbenzylamine used in step (a) is R- α -methylbenzylamine; in step (b), R is H; and in step (C), R is H, and the solvent used is selected from C_1-3Alcohol, C_2-4Carboxylic acids and mixtures thereof.

[3] In a more preferred embodiment, the hydrogenation step (b) is carried out under the conditions of (bi); and the combination of (a) and (b),

hydrogenation step (C) at C_1-3Alcohols with C_2-4In a mixture of acids, wherein the ratio of alcohol to acid is from 30: 1 to 1: 10.

[4] In a more preferred embodiment, the hydrogenation step (bi) is carried out at a hydrogen pressure of 0.01-2 psi at a temperature of 20-60 ℃ for 3-24 hours; and

in the hydrogenation step (c), the alcohol used is selected from methanol and ethanol, the acid is acetic acid and the ratio of alcohol to acid is from 30: 1 to 1: 1.

[5] In a further preferred embodiment, the hydrogenation step (bi) is carried out at a hydrogen pressure of 0.01-1 psi at a temperature selected from room temperature or 50-60 ℃ for 3-12 hours; and

the hydrogenation step (c) is carried out in ethanol and acetic acid in a ratio of from 20: 1 to 8: 1.

[6] In another further preferred embodiment, the hydrogenation step (bi) is carried out at a hydrogen pressure of 0.01-1 psi at a temperature selected from room temperature or 50-60 ℃ for 3-12 hours; and

the hydrogenation step (c) is carried out in methanol and acetic acid in a ratio of from 20: 1 to 8: 1.

[7] In another more preferred embodiment, in step (c), from 1 to 4 equivalents of acid based on the amount of IV are present.

[8] In another more preferred embodiment, in step (c), about 2 equivalents of acid based on the amount of iv are present.

[9] In another more preferred embodiment, the hydrogenation step (b) is carried out under (bi) conditions of 10-1000 psi hydrogen pressure and 60-80 ℃ temperature for 3-24 hours.

[10] In another further preferred embodiment, the hydrogenation step (bi) is carried out at a hydrogen pressure of 50-500 psi.

[11] In another more preferred embodiment, the hydrogenation step (b) is carried out under conditions (bii); and the combination of (a) and (b),

[12] In a more preferred embodiment, the hydrogenation step (bii) is carried out at a first temperature of 20-30 ℃ for about 3-6 hours and then at a second temperature of 60-80 ℃ for about 6-18 hours under a hydrogen pressure of 50-500 psi; and the combination of (a) and (b),

[13] In a more preferred embodiment, the hydrogenation step (bii) is carried out at a first temperature of 20-30 ℃ for about 3-6 hours and then at a second temperature of 60-80 ℃ for about 10-15 hours under a hydrogen pressure of 50-500 psi; and the combination of (a) and (b),

[14] In a further preferred embodiment, the hydrogenation step (bii) is carried out at a first temperature of about room temperature for about 3,4,5 or 6 hours at 100-300psi of hydrogen pressure, followed by a second temperature of 65-75 ℃ for about 10,11,12,13,14 or 15 hours; and the combination of (a) and (b),

[15] In a further preferred embodiment, the hydrogenation step (bii) is carried out at a first temperature of about room temperature for about 3,4,5 or 6 hours at 100-300psi of hydrogen pressure, followed by a second temperature of 65-75 ℃ for about 10,11,12,13,14 or 15 hours; and the combination of (a) and (b),

[16] In another more preferred embodiment, in step (c), from about 1 to about 4 equivalents of acid based on the amount of IV are present.

[17] In another more preferred embodiment, in step (c), about 2 equivalents of acid based on the amount of iv are present.

[18]In a second embodiment, the present invention provides a method of synthesizing a compound of formula i:

the method comprises the following steps:

(d) reacting a compound of formula v:

with chiral methylbenzylamine to form a compound of formula vi:

wherein R is H, OH or OCH₃；

(e) Contacting a compound of formula vi, or a stereoisomer or salt form thereof, with allylmagnesium bromide to form a compound of formula vii, or a diastereomer or salt form thereof:

wherein R is H, OH or OCH₃And the diastereomeric excess obtained is at least 75%; and the combination of (a) and (b),

(f) in the presence of palladium-carbon, at C_1-3Alcohol and C_2-4Hydrogenating a compound of formula VII, or a diastereomer or salt form thereof, in a carboxylic acid to form a compound of formula I, or a stereoisomer or salt form thereof;

with the proviso that no cerium reagent is used in step (e).

[19] In another preferred embodiment, the chiral methylbenzylamine used in step (d) is S-phenylglycinol and R in steps (e) and (f) is OH.

[20] In another more preferred embodiment, the diastereomeric excess obtained in step (e) is at least 85%; and the combination of (a) and (b),

in step (f), the alcohol used is selected from methanol and ethanol, the acid is acetic acid, and the ratio of alcohol to acid is from 10: 1 to 1: 10.

[21] In another more preferred embodiment, the diastereomeric excess obtained in step (e) is at least 90%; and the combination of (a) and (b),

in step (f), the alcohol used is ethanol and the ratio of alcohol to acid is from 10: 1 to 1: 1.

[22] In another more preferred embodiment, the diastereomeric excess obtained in step (e) is at least 90%; and the combination of (a) and (b),

in step (f), the alcohol used is methanol and the ratio of alcohol to acid is from 10: 1 to 1: 1.

[23] In another more preferred embodiment, tetrahydrofuran is used as solvent in step (e).

[24]In a third embodiment, the present invention provides a novel compound of formula iv:

wherein R is selected from H, OH and OCH₃。

[25] In another preferred embodiment, R is H.

[26] In another more preferred embodiment, the compound of formula iv is in the mandelate form.

[27]In a fourth embodiment, the present invention provides novel compounds of formula vii:

wherein R is selected from H, OH and OCH₃。

[28] In another preferred embodiment, R is OH.

[29] In another more preferred embodiment, the compound of formula VII is in the form of the tartrate salt.

The reactions of the synthetic methods of the present invention are carried out in suitable solvents readily selected by those skilled in the art of organic synthesis, unless otherwise specified. Such suitable solvents are generally any solvent which does not substantially react with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out, i.e., can be a temperature in the range from the freezing point of the solvent to the boiling point of the solvent. For a given reaction, the reaction may be carried out in one solvent or a mixture of solvents. Depending on the particular reaction step, a suitable solvent for this particular reaction step may be selected.

Suitable ethereal solvents include: dimethoxymethane, tetrahydrofuran, 1,3 dioxane, 1, 4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, or tert-butyl methyl ether.

"Stable compound" and "stable structure" refer to a compound that is sufficiently isolated from a reaction mixture to be of effective purity and formulated into an effective therapeutic preparation.

The compounds described herein may have asymmetric centers. All chiral compounds, diastereomers and racemic forms are included in the present invention. Olefins, geometric isomers such as C = N double bonds, and the like may also be present in the compounds described herein, and all such stable isomers are included within the scope of the present invention. It will be appreciated that certain compounds of the invention contain asymmetrically substituted carbon atoms, which may be isolated in optically active or racemic forms. Also, it should be recognized that cis and trans geometric isomers of the compounds of the present invention are also described and may be isolated as mixtures of isomers or as isolated isomers. Except where specific stereochemistry or isomeric forms are specifically indicated, the present invention includes all chiral compounds, diastereomers, racemic forms, and all geometric isomers.

The term "salt" as used in the present invention refers to a compound which has been reacted with a chiral or achiral organic acid or with an inorganic acid. Chiral and achiral organic acids are well known in the art, examples of which include, but are not limited to, mandelic acid, tartaric acid, oxalic acid, and p-toluenesulfonic acid. Inorganic acids are also well known in the art, examples of which include, but are not limited to, hydrochloric acid, phosphoric acid, and sulfuric acid.

The alcohol used herein is preferably C_1-3Alcohols, i.e., methanol, ethanol, n-propanol, and isopropanol. Methanol or ethanol is preferred. By carboxylic or dicarboxylic acids is meant C_2-4A carboxylic or dicarboxylic acid; examples thereof include, but are not limited to, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid and succinic acid, preferably acetic acid.Aromatic carboxylic acids refer to carboxylic acids attached to a benzene ring, such as benzoic acid.

As used herein, "alcohol to acid ratio" refers to volume ratio.

Chiral methylbenzylamine as used herein refers to an R or S stereoisomer having the following structure:

wherein R is H, OH or OCH₃. Examples thereof include, but are not limited to, R- α -methylbenzylamine, S-phenylglycine and R-phenylglycine, preferably R- α -methylbenzylamine or S-phenylglycine.

The cerium reagents used herein include cerium compounds known to those skilled in the art to be effective lewis acid chelating agents in grignard addition reactions. By "effective" is meant a situation that provides enhanced selectivity of the grignard addition reaction as compared to a reaction without the use of a cerium reagent. Such cerium reagents include in particular cerium chloride and, in addition, organic cerium reagents.

The present invention is expected to be practiced at least on the gram scale, kilogram scale, and industrial scale. As used herein, a "gram-scale" preferably refers to a scale wherein the amount of at least one starting material is 10 grams or more, more preferably at least 50 grams or more, more preferably at least 100 grams or more. As used herein, "kilogram scale" refers to a scale wherein at least one of the starting materials is used in an amount greater than 1 kilogram. As used herein, "industrial scale" refers to a scale that is not laboratory scale and is sufficient to provide a scale sufficient for clinical trials or sale.

As used herein, "high yield" means that the overall yield of product from starting materials is at least 45%, preferably 50%, more preferably 55%, and even more preferably 60% of theoretical yield.

Synthesis of

As a non-limiting example, the present invention may further utilize the flows shown belowScheme 1 illustrates. This scheme details the general synthetic procedures for preparing compounds of formula I or stereoisomers or pharmaceutically acceptable salts thereof from compounds of formulae II and V.

The hydrochloride of compound i is represented herein by la; the SR diastereomer of compound IV is represented by IVa, the mandelate salt by IVb and the hydrochloride salt by IVc. For compound VII, the tartrate salt is represented by VIIa and the SS diastereomer is represented by VIIb.

The above scheme (R = H, OH or OCH)₃) And the following description refers to R- α -propyl-piperonyl amine only. However, it will be readily appreciated by those skilled in the art that the present invention can be used not only for the R enantiomer but also for the preparation of the S enantiomer, depending on the enantiomer of the chiral amine used in step a or d. Thus, the above scheme and the following description are not limited to R- α -propyl-piperonyl amine, but are used to generally describe the synthesis of R and S- α -propyl piperonyl amine.

In a first embodiment, the present invention relates to a process for the preparation of a compound of formula i by steps a, b and c as indicated above.

The compounds II can be prepared from known precursors by known methods. For example, in gaseous BF₃1, 3-benzodioxole (available from Aldrich chemical) is readily converted to II by reaction with butyric anhydride in dichloroethane.

Step a

Imine iii can be formed from ketone ii by the following reaction: and reacting the II with chiral methylbenzylamine in the presence of triethylamine, titanium tetrachloride and toluene under reflux conditions. Preferably, R- α -methylbenzylamine is used as chiral amine. It will be understood by those of ordinary skill in the art that when R is OH or OCH₃To obtain III, it will be necessary to use the corresponding substituted R- α -methylbenzylamine. It is preferred to use at least a stoichiometric amount of chiral amine (based on the amount of ketone II). Also can be used forAn excess of chiral amine is used to increase the yield or reduce the reaction time. Other dehydration conditions known to those skilled in the art may also be used for the reaction of imine III from ketone II. Mixtures of E and Z isomers of iii are expected, although the major product is the E isomer.

Step b

The selective hydrogenation of III to IV can be carried out using Ra-Ni catalysts. Preferably, from 1 to 15 wgt% of catalyst is used, more preferably from 5 to 10 wgt%, more preferably about 10 wgt%, based on the amount of III present. Classes of solvents that can be used for this step include, but are not limited to, tetrahydrofuran, methanol, ethanol, and toluene. Ethanol or methanol is preferably used as solvent. Combinations of different solvents may also be used. For example, a 1: 9 combination of toluene and ethanol may be used. It is also possible to use smaller or larger amounts of toluene, for example from 10: 1 to 1: 10, but the reaction rate generally becomes slower with increasing amounts of toluene.

Step b can be carried out at the same temperature or at two different temperatures and the temperature can be from-78 to 150 c, preferably from 0 to 100 c. When the same temperature is used, it is preferably 0 to 70 ℃, more preferably 20 to 60 ℃, and even more preferably room temperature or 50,51,52,53,54,55,56,57,58,59 or 60 ℃. If the same temperature is used, the hydrogen pressure is preferably 0.01 to 10 psi, more preferably 0.01 to 2 psi, and still more preferably 0.01 to 1 psi. When the same temperature is used, the reaction time is preferably 2 to 30 hours, more preferably 3 to 24 hours, and still more preferably 3,4,5,6,7,8,9,10,11 or 12 hours.

The purpose of using a low hydrogen pressure (i.e.. ltoreq.10 psi) for the reduction reaction at the same temperature is because the applicants have found that increasing the pressure reduces the stereoselectivity. As further illustrated in example 1 below, 86% diastereoselectivity was obtained at room temperature when hydrogenolysis was performed using hydrogen pressure < 1 psi. Conversely, if the same conditions were used but the hydrogen pressure was increased to 50psi, the diastereoselectivity decreased to only 75%.

If the reaction temperature is from 60 to 100 ℃, preferably from 60 to 80 ℃, more preferably from 60,62,64,66,68,70,72,74,76 or 80 ℃, step b can also be carried out at the same temperature under a higher hydrogen pressure. At these temperatures, hydrogen pressures of from 10 to 3000psi, preferably from 10 to 1000 psi, more preferably from 50 to 500psi, can be used. When the same temperature is used, the preferred reaction time is 2 to 30 hours, more preferably 3 to 24 hours, and still more preferably 3,4,5,6,7,8,9,10,11, or 12 hours. As described above, the use of high pressure hydrogen is advantageous because the high pressure reaction can reduce the loading of the catalyst compared to the low pressure reaction.

When two different temperatures are used, the reaction is carried out in two stages. The first stage is preferably carried out at a temperature of from 0 to 35 deg.C, more preferably from 20 to 30 deg.C, and even more preferably at room temperature. The first stage is preferably carried out for 2 to 8 hours, more preferably 3 to 6 hours, more preferably 3,4,5 or 6 hours. The second stage is preferably carried out at a temperature of from 40 to 100 deg.C, more preferably from 60 to 80 deg.C, more preferably from 65 to 75 deg.C, even more preferably at a temperature of 65,66,67,68,69,70,71,72,73,74 or 75 deg.C. The second stage is preferably carried out for 2 to 24 hours, more preferably 6 to 18 hours, still more preferably 10 to 15 hours, and further preferably 10,11,12,13,14 or 15 hours. The hydrogen pressure is preferably from 0.01 to 3000psi, more preferably from 50 to 500psi, still more preferably 100-300 psi. As known to those of ordinary skill in the art, it is commercially preferred to use hydrogen pressures above 10 psi. This advantageously reduces the amount of catalyst loading and allows for simpler or at least more accessible equipment, thereby saving money. Preferably, the reaction is heated to the second stage temperature after the first stage. The heating may be carried out by methods known to those skilled in the art.

The inventors have found that the reason why the hydrogenation step according to the invention at two different temperatures gives a higher diastereoselectivity is that Raney nickel/H is used₂The reduction is carried out at a much faster rate for trans-imines of III than for cis-imines. Due to K_asAnd K_asThe temperature is very dependent, so that a slight increase in temperature leads to isomerization of the cis-imine to the trans-imine, which is then rapidly reduced. This is illustrated in the following scheme.

The hydrogenolysis reaction is first carried out at a temperature of about room temperature to reduce most of the trans-imine present. The temperature is then increased to promote interconversion of the two isomers. When trans-imines are formed, they are rapidly reduced. Thus, high diastereoselectivity is obtained.

The diastereomeric excess de (ratio of RR to SR (corresponding to compounds IV and IVa, respectively)) obtained in step c is preferably at least 80% (up to 100%), more preferably at least 85%, more preferably at least 90%. The reaction time depends on a variety of variables including hydrogen pressure, solvent and temperature. The reaction can be monitored using standard HPLC techniques to determine the reaction time for complete imine hydrogenation.

After IV is formed, its diastereomeric purity can be increased by salt formation with an organic acid. For example, crude or impurity-containing iv can be diastereoisomerically purified as follows: they were dissolved in acetonitrile, S-mandelic acid was added and the mandelate salt precipitated was collected. Other acids known to those skilled in the art, including chiral and achiral acids (e.g., oxalic acid) and inorganic acids, may also be used, provided that the resulting salt forms crystals.

Step c

In step c, not only the free base IV but also a salt thereof, i.e. the mandelate salt (IVc), may be used. It should be noted, however, that certain salts limit the effectiveness of this step and should therefore be avoided. For example, the HBr salt of IV is difficult to debenzylate and should preferably be avoided. Since step c involves another hydrogenation step using a different catalyst (but similar solvents), it is desirable to carry out step c directly avoiding the formation of salts. Such a process provides a process that minimizes the amount of solvent used and minimizes product loss due to crystallization. Preferably, the catalyst is removed between each step so that the catalyst is recycled.

The conversion of IV to I can be achieved by using Pd/C, preferably 10% Pd/C, as catalyst and preferably hydrogenating IV at room temperature. Preferably, 5 to 25 wt% of catalyst is used, more preferably 10 to 20 wt%, more preferably about 15 wt%, based on the amount of IV present. The hydrogen pressure is preferably 0.01 to 1000 psi, more preferably 10 to 200 psi. As the solvent, a combination of an alcohol selected from methanol, ethanol and isopropanol and a carboxylic acid selected from acetic acid and propionic acid is preferably used, and a combination of ethanol and acetic acid or methanol and acetic acid is more preferred. The alcohol or acid may be used separately. The ratio of alcohol to acid is preferably from 30: 1 to 1: 10, more preferably from 30: 1 to 1: 1, and most preferably from 20: 1 to 8: 1. Also preferably from 1 to 4 equivalents of acid, more preferably 2 equivalents, based on IV are present. As in the case of step b, the reaction time also depends on how the above variables are selected. The removal of the phenylethane can be monitored using standard HPLC techniques. Preferably step c is carried out for 2 to 48 hours, more preferably 4 to 9 hours. The ee value of I obtained in this step is preferably at least 70%, more preferably at least 85%.

After I has been formed, it is advantageous to form them as the hydrochloride (Ia) immediately in order to increase the ee value. The compound I obtained after hydrogenation in the presence of palladium-charcoal is dissolved in toluene, isopropanol or a mixture thereof, and hydrochloric acid or HCl/isopropanol is added to precipitate the hydrochloride thereof. The enantiomeric excess (ee) of Ia can be further increased by reslurrying in isopropanol and n-heptane. Preferably, a 5-6N HCl/isopropanol solution is added to the toluene solution of I.

In a second embodiment, the present invention provides a process for the preparation of a compound of formula I by steps d, e and f as indicated above.

Step d

Piperaldehyde compound V is known and commercially available from Aldrich chemical company. The formation of the imine VI can be accomplished by contacting V under dehydrating conditions with a suitable chiral amine. Preferably the reaction is carried out using a dean Stark trap under reflux conditions together with S-phenylglycinol (when R = OH), p-toluenesulfonic acid, and toluene. At least a stoichiometric amount of chiral amine is preferably used, based on the amount of aldehyde used. The use of an excess of chiral amine may increaseYield or reduced reaction time. It will be readily understood by those skilled in the art that the compounds of formula (I) wherein R is H or OCH₃VI, the corresponding methylbenzylamine will need to be used. Other dewatering conditions known to those skilled in the art may also be used. As with compound III, it is expected that the E isomer of V will predominate, although the formation of both isomers would be expected.

Step e

VI can be converted to VII using allylmagnesium chloride, either purchased from Aldrich chemical company or prepared according to methods known to those skilled in the art. The reaction is carried out with high diastereoselectivity and high yield (about 72-82%). The de for this reaction is preferably at least 75%, more preferably at least 85%, more preferably at least 90%. The reaction requires at least a stoichiometric amount of grignard reagent (based on imine). It is preferred to use an excess of Grignard reagent to facilitate the reaction. For example, a 1.5,2,2.5,3,3.5,4,4.5,5 or more fold excess of Grignard reagent may be used, preferably a 2.5 fold excess. Standard grignard solvents known to those skilled in the art can be used, for example, the ethers described above, preferably THF. The temperature of the Grignard addition reaction is preferably 20 to 30 ℃, and more preferably about room temperature. In view of the nature of the Grignard reagent, it is necessary to maintain the preferred reaction temperature by slow addition of the Grignard reagent, cooling the reaction, or both. The reaction time is preferably 1 to 5 hours, more preferably 2 to 3 hours.

Preferably, step (e) does not use a lewis acid chelating agent, for example a cerium reagent (e.g. cerium chloride). The conditions of the invention favor diastereoselective introduction of the allyl group without the need to use Lewis acid chelating agents such as ZnCl₂,TiCl₄,BF₃-O(Et)₂,CuI,CuBr₂-S(CH₃)₂And cerium reagents (e.g., CeCl)₃) To increase the selectivity. For the grignard addition reaction, a cerium reagent is generally used as a chelating agent to increase the selectivity. Unfortunately, the use of cerium reagents is often avoided in the industry due to the difficulty of handling the reagents. Therefore, the present invention does not makeThe addition step with a cerium reagent is superior to addition steps described in the literature and in the background section of the invention that require cerium or other lewis acid chelating agents to increase grignard selectivity.

Immediately after the vii is formed, their de values can be increased by contacting them with an organic acid to form a salt, which can precipitate and be easily isolated. For example, VII may be dissolved in acetonitrile, isopropanol or ethyl acetate (preferably acetonitrile) and tartaric, oxalic or maleic acid, preferably tartaric acid, added. The tartrate salt of VII is preferably formed in acetonitrile, since this salt readily precipitates from acetonitrile. The de value of VII can also be increased by crystallization of the free base, preferably using ethyl acetate and n-heptane.

Neither magnesium propyl chloride nor lithium propyl are suitable for use in the present invention. Propyl magnesium chloride results in a lower yield of about 50%. Propyllithium provides only about 60% de. Thus, both reagents lead not only to lower yields, but also to poorer diastereoselectivity.

Step f

Hydrogenation of the vii in the presence of palladium-on-carbon (preferably 10% Pd/C) removes 2-phenylethyl alcohol (R = OH) and produces i. Preferably, the catalyst is used in an amount of 5 to 25 wgt%, more preferably 10 to 20 wgt%, and even more preferably about 15 wgt% of the amount VI present. The hydrogen pressure used is preferably from 0.1 to 10 psi, more preferably from 1 to 5 psi, even more preferably 2,3 or 4 psi. The reaction temperature is preferably room temperature. The progress of the reaction can be monitored by HPLC. The preferred hydrogenation time is 24 to 48 hours. As the solvent, a combination of an alcohol selected from methanol, ethanol and isopropanol and a carboxylic acid selected from acetic acid and propionic acid is preferably used, and a combination of ethanol and acetic acid or methanol and acetic acid is more preferred. The ratio of alcohol to acid is preferably from 10: 1 to 1: 10, more preferably from 10: 1 to 1: 1, even more preferably from 8: 1 to 3: 1. The olefinic bond of the propylene side chain is very readily reduced, resulting in a "reduced" VII, which is subsequently debenzylated. To ensure complete conversion of VII to I, additional catalyst may be added.

After I has been formed, they are preferably immediately converted into their HCl salts. The compound I obtained after the hydrogenation in the presence of palladium-on-carbon can be dissolved in toluene, isopropanol or a mixture thereof, and hydrochloric acid or HCl/isopropanol can be added to precipitate the hydrochloride salt thereof. The ee of I is then further increased by recrystallization from isopropanol and n-heptane. Preferably, a 6N HCl/isopropanol solution is added to the toluene solution of I and the resulting solid is isolated.

Other features of the present invention will become apparent in the course of the following description of the embodiments. The examples given therein are merely illustrative of the invention and the invention is not limited thereto.

Examples

Example 1

Step a:

preparation of (R) -N- [1- (1, 3-benzodioxol-5-yl) butylidene ] - α -methylbenzylamine (III) (R = H)

In a 22L reaction flask equipped with an overhead stirrer, water condenser, nitrogen inlet, 2L addition funnel, temperature probe, ii (R = H) (1Kg,5.2M), toluene (10L), R- (+) - α -methylbenzylamine (816mL,6.35M), and triethylamine (1836mL,13.2M) were placed in that order and cooled to 5 ℃. Under vigorous stirring, a solution of titanium (IV) chloride (320mL in 1L of toluene) was added slowly through a 2L addition funnel, while maintaining the temperature below 15 ℃. The addition was carried out for 1-2 hours. After the addition was complete, the reaction mass was stirred at room temperature for 1 hour and then heated to mild reflux (111 ℃) with vigorous stirring for 4 hours. The reaction mass was cooled to room temperature and filtered through celite to remove solids (TiO)₂And Et₃NHCl), the filter cake was washed with toluene (4L). The toluene solution was washed with a 10% cold solution of sodium hydroxide (1X 2.5L) and a saturated aqueous solution of NaCl (2X 2L). The solution was dried over sodium sulfate and concentrated in vacuo to give an oil (1524g, 96)2 wt%, yield 95%).

Step b: preparation of [ R- (R)^*,R^*]-N- (1' -phenylethyl-alpha-propyl-1, 3-benzodioxole-

5-Methylamine (S) - α -Hydroxyphenylacetate (IVb) (R = H)

A slurry of iii (R = H) (1459g) and Ra-Ni (wet.500g) in 10L ethanol was hydrogenated at room temperature for 5-16 hours with hydrogen gas being passed and then further hydrogenated at 50-60 ℃ for 5 hours. The catalyst was filtered off and washed with ethanol (1.5L). The filtrate was concentrated by rotary evaporation to give IV as an oil (1280g) which was then crystallized from S-mandelic acid (836g,5.5M) in 6L acetonitrile. The precipitated solid was filtered and washed with 2L of cold acetonitrile and 2L of cold heptane to give IVb (1784g,99.4 wt%, 80% yield).

The stereoselectivity of step b of the process using different catalysts, temperatures and hydrogen pressures was compared. Except for D, in which THF was used as solvent, ethanol was used as solvent in all cases. The results are shown in table 1 below.

Table 1: stereoselectivity of imine reduction reactions

Catalyst temperature H₂de remark

(℃) (psi)1 Ra-Ni 25 ＜1 862 Ra-Ni 55 ＜1 893 Ra-Ni 0-25 ＜1 884 Ra-Ni 25&65 ＜1 94 5h/25℃ & 5h/65℃5 Ra-Ni 23&70 150 91 6h/23℃ & 14h/70℃A Ra-Ni 25 50 75B NaBH₄ -40-25 - 50C Pd/C 25 ＜1 67D Pd/C 25 ＜1 67

As can be seen, hydrogenation at high pressure but not high temperature (comparative example A) resulted in a more than two-fold decrease in diastereoselectivity compared to the present invention. In addition, with Pd/C (comparative examples C and D) or NaBH₄(comparative example B) substitution of Ra-Ni also resulted in reduced diastereoselectivity.

Step b can also be carried out directly without isolation of IV. The absence of isolation of IV reduces product loss due to crystallization and also reduces the amount of additional solvent required.

An alternative step b:

preparation of [ R- (R)^*,R^*]-N- (1' -phenylethyl-alpha-propyl-1, 3-)

Benzodioxole-5-methanamine (IV) (R = H)

III (15g) and Ra-Ni (wet,2.2g) were hydrogenated in a slurry of 140mL ethanol under hydrogen (150 psi) at room temperature for 6 hours, then at 70 ℃ for a further 14 hours. The catalyst was filtered off and washed with ethanol (20mL) to give a solution of IV (12.8g, 85%) in approximately 150mL of ethanol.

Step c:

preparation of (R) -alpha-propyl-1, 3-benzodioxole-5-methanamine hydrochloride

(Ⅰa)

In a 22L reaction flask equipped with an overhead stirring device, dispersion tube and thermocouple were placed in sequence iv (R = H) (1776g), acetic acid (7L), Pd/C (10%) (50% water) (450g), and ethanol (7L). Hydrogen was passed through for 24-26 hours under stirring, and then the catalyst was filtered off. The filtrate was concentrated in vacuo to a small volume and then dissolved in toluene (10L). The toluene solution was washed with 10% NaOH (1X 10L and 1X 5L) and water (3X 3L). Concentrated hydrochloric acid (36-38%, 450mL) was then added to form a slurry. The solid was filtered and the filter cake was washed with cold toluene (2L) to give ia (R = H) (873g,99.4 ee%, 100 wt%, 96% yield).

Step c tests were performed under various conditions. The results are shown in table 2 below.

Table 2: stereoselective debenzylation

Conditional% conversion Note 1 free base, EtOH/AcOH (8: 1),20hr 1002 free base, EtOH/AcOH (3: 1),20hr 1003 free base, EtOH,20 hr 874 free base, AcOH,20 hr 825 free base, AcOH/EtOH (1: 1),20hr 93

6 free base, propionic acid/EtOH (1: 1) 100

7 mandelate, AcOH/EtOH (1: 1),21hr 97.5

8 free base, AcOH (2eq)/EtOH (1: 1),7hr 100

A Pd/C(10％),HCO₂NH₄MeOH, reflux 100 part racemization

HBr salt, AcOH/EtOH (1: 1),20hr < 5

Comparative examples A and B were carried out using the conditions described by Bringmann et al in Leibigs ann. chem.1990,795, p.799. As can be seen, both processes are not very suitable, since the products obtained are partly racemized (comparative example A) or only very low yields are obtained (comparative example B).

EXAMPLE 2 preparation of (R) -alpha-propyl-1, 3-benzodioxole-5-methanamine hydrochloride (Ia)

(R) -N- [1- (1, 3-benzodioxol-5-yl) butylidene ] - α -methylbenzylamine, prepared as described in example 1 step a from 500g of II (R = H) and 816ml of (R) - (+) - α -methylbenzylamine, was dissolved in ethanol (6L) together with Ra-Ni (250g, wet syrup) and hydrogenated at 23 ℃ for 5 hours and then at 60-65 ℃ for a further 5 hours. The catalyst was filtered off and washed with ethanol (0.5L). To the ethanol solution was added 0.5L of acetic acid and Pd/C (10%) (50% water) (250 g). Hydrogen was passed for 23 hours under stirring, and then the catalyst was filtered off. The filtrate was concentrated in vacuo to a small volume and then dissolved in toluene (5L). The toluene solution was washed with 10% NaOH (1X 3L and 1X 2L) and water (2X 1.5L). Then HCl/isopropanol solution (5-6N,0.7L) was added to form a slurry. The solid was filtered and the filter cake was washed with cold toluene (2L) to give the crude product (97.2% ee). The crude product was then slurried again in isopropanol (2L) and n-heptane (4L). The solid was filtered and washed with n-heptane (2L) to give ia (R = H) (391.1g, 99.1% ee).

Example 3

Step d:

preparation of (R) -E-beta- ((1, 3-benzodioxole-5-)

Benzylidene) amino) phenethyl alcohol (VI) (R = OH)

A solution of piperonal (2.3Kg), (D) -phenylglycinol (2.1Kg) and p-toluenesulfonic acid (2.5g) in toluene (13L) was heated to reflux using a dean-Stark trap with water separation and continued to separate throughout the reaction. Once the theoretical amount of water has been collected (3-4 hours), it is used¹H-NMR analysis reaction. The reaction mass was cooled to about 80-85 ℃. Heptane (8L) was added slowly and the resulting solution was further cooled to 5-10 ℃ and aged for about 1 hour. During cooling, a precipitate was observed to appear when the temperature was reduced to about 60 ℃. The product was isolated by filtration and dried to constant weight under vacuum at 50-55 deg.C to give 3.8Kg VI (R = OH) (95%) as a highly crystalline solid. Of the product¹H-NMR was the same as that of the true sample.

Step e:

preparation of (R) -beta- (((1, 3-benzodioxol-5-yl) -

3-butenyl) amino) phenethyl alcohol tartrate (viia) (R = OH)

A2M solution of allylmagnesium chloride in THF (9.4L) was added dropwise over about 2 hours to a cold solution of VI (R = OH) (2.02Kg) in THF (9.5L) (10-15 deg.C). The dropping rate was controlled to maintain the temperature below 30 ℃. The resulting mixture was aged for about 1.0hr, cooled to 5-10 deg.C, and quenched by slow addition of 30% aqueous acetic acid (14L) while maintaining the temperature below 30 deg.C. The organic phase was separated and treated with 20% aqueous sodium hydroxide until the pH stabilized around 8. The layers were separated and the organic solution was washed with 10% aqueous sodium chloride and then concentrated under reduced pressure to give an oil (89.5% de). To isolate the tartrate salt form, acetonitrile (15L) was added followed by tartaric acid (1 eq.1.1 Kg). The mixture was warmed to 50-55 deg.C, aged for about 1 hour, then slowly cooled to room temperature over 2-4 hours. After aging for 1-2 hours at this temperature, the product was filtered, washed with acetonitrile (-10L), dried to constant weight under vacuum at 45-50 ℃ to give vii-tartrate (R = OH) (2.6Kg, 82%) as an off-white solid (98.8% de).

Step f: preparation of (R) -alpha-propyl-1, 3-benzodioxole-5-methanamine hydrochloride (Ia)

A degassed solution of vila (R = OH) (2.5Kg) in methanol (9L) and acetic acid (5L) was transferred under pressure to a "wet" slurry of 10% palladium-on-charcoal (-50% moisture, 0.8Kg) in methanol (9L) and acetic acid (4.5L). The resulting slurry was hydrogenated at room temperature under 1-3 psi of hydrogen for 48 hours. Samples were taken for analysis. The progress of the reaction was followed by HPLC. Once the reaction was complete, the used catalyst was removed by filtration and washed with methanol. The filtrates were combined and concentrated under reduced pressure and the resulting residue was partitioned between toluene (4L) and 1N aqueous hydrochloric acid (. about.5L). The aqueous phase was separated and basified with 30% aqueous sodium hydroxide in the presence of toluene (7L) to pH 13. The layers were separated and the aqueous layer was extracted with toluene (5L). The combined organic solutions were washed with 20% aqueous sodium chloride and purified by celite pad. The toluene solution was then cooled to 10-15 ℃ and a 6N HCl/isopropanol (1.1 eqs.) solution was added slowly at a rate that maintained the temperature below 20 ℃. The resulting slurry was aged at room temperature for 1 hour and then filtered. The resulting solid was washed with toluene and then dried in a vacuum oven at 50-55 ℃ to constant weight to give 2.05Kg (82% yield) of I as a white loose solid. The product has excellent enantiomeric purity (> 99.5% ee) and was determined in wt.% (> 98% (HPLC)).

Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims

1. A method of synthesizing a compound of formula i or a stereoisomer or salt form thereof:the method comprises the following steps: (a) reacting a compound of formula II:with chiral methylbenzylamine to form a compound of formula iii:

wherein R is selected from H, OH and OCH₃；

2. The process according to claim 1, wherein in step (a) the chiral methylbenzylamine is R- α -methylbenzylamine, in step (b) R is H, and in step (C) R is H, and the solvent used is selected from C_1-3Alcohol, C_2-4Carboxylic acids and mixtures thereof.

3. The process according to claim 2, wherein the hydrogenation step (b) is carried out under (bi) conditions of 0.01 to 10 psi hydrogen pressure; and the combination of (a) and (b),

4. A process according to claim 3, wherein the hydrogenation step (bi) is carried out at a hydrogen pressure of 0.01-2 psi at a temperature of 20-60 ℃ for 3-24 hours; and

5. The process according to claim 4, wherein the hydrogenation step (bi) is carried out at a hydrogen pressure of 0.01-1 psi at a temperature selected from room temperature or 50-60 ℃ for 3-12 hours; and

6. The process according to claim 4, wherein the hydrogenation step (bi) is carried out at a hydrogen pressure of 0.01-1 psi at a temperature selected from room temperature or 50-60 ℃ for 3-12 hours; and

7. A process according to claim 3, wherein in step (c) from 1 to 4 equivalents of acid based on the amount of iv are present.

8. A process according to claim 3 wherein in step (c) about 2 equivalents of acid based on the amount of iv are present.

9. The process according to claim 2, wherein the hydrogenation step (b) is carried out under (bi) conditions of a hydrogen pressure of 10-1000 psi and a temperature of 60-80 ℃ for 3-24 hours.

10. The process according to claim 9, wherein the hydrogenation step (bi) is carried out at a hydrogen pressure of 50-500 psi.

11. The process according to claim 1, wherein the hydrogenation step (b) is carried out under (bii) conditions; and the combination of (a) and (b),

12. A process according to claim 11, wherein the hydrogenation step (bii) is carried out at a first temperature of from 20 to 30 ℃ for from about 3 to 6 hours and then at a second temperature of from 60 to 80 ℃ for from about 6 to 18 hours under a hydrogen pressure of from 50 to 500 psi; and the combination of (a) and (b),

13. A process according to claim 12, wherein the hydrogenation step (bii) is carried out at a first temperature of from 20 to 30 ℃ for from about 3 to 6 hours and then at a second temperature of from 60 to 80 ℃ for from about 10 to 15 hours under a hydrogen pressure of from 50 to 500 psi; and the combination of (a) and (b),

14. The process according to claim 13, wherein the hydrogenation step (bii) is carried out at a first temperature of about room temperature for about 3,4,5 or 6 hours at 100-300psi of hydrogen pressure, followed by a second temperature of 65-75 ℃ for about 10,11,12,13,14 or 15 hours; and the combination of (a) and (b),

15. The process according to claim 13, wherein the hydrogenation step (bii) is carried out at a first temperature of about room temperature for about 3,4,5 or 6 hours at 100-300psi of hydrogen pressure, followed by a second temperature of 65-75 ℃ for about 10,11,12,13,14 or 15 hours; and the combination of (a) and (b),

16. The process of claim 11 wherein in step (c) from about 1 to about 4 equivalents of acid based on the amount of iv are present.

17. The process of claim 11 wherein in step (c) about 2 equivalents of acid based on the amount of iv are present.

18. A method of synthesizing a compound of formula i or a stereoisomer or salt thereof:the method comprises the following steps: (d) reacting a compound of formula v:

with chiral methylbenzylamine to form a compound of formula vi:

wherein R is H, OH or OCH₃；

with the proviso that no cerium reagent is used in step (e).

19. The process according to claim 18, wherein the chiral methylbenzylamine used in step (d) is S-phenylglycinol and R in steps (e) and (f) is both OH.

20. The process according to claim 19, wherein in step (e), the diastereomeric excess obtained is at least 85%; and the combination of (a) and (b),

21. The process according to claim 20, wherein in step (e), the diastereomeric excess obtained is at least 90%; and the combination of (a) and (b),

22. The process according to claim 20, wherein in step (e), the diastereomeric excess obtained is at least 90%; and the combination of (a) and (b),

23. The process according to claim 19, wherein tetrahydrofuran is used as solvent in step (e).

24. A compound of formula IV:

wherein R is selected from H, OH and OCH₃。

25. The compound according to claim 24, wherein R is H.

26. A compound according to claim 25, wherein the compound of formula iv is in the mandelate salt form.

27. A compound of formula VII or a stereoisomer or salt form thereof:

wherein R is selected from H, OH and OCH₃。

28. The compound according to claim 27, wherein R is OH.

29. A compound according to claim 28, wherein the compound of formula vii is in the form of the tartrate salt.