WO2013073525A1

WO2013073525A1 - Industrial method for producing optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidines

Info

Publication number: WO2013073525A1
Application number: PCT/JP2012/079380
Authority: WO
Inventors: 英之鶴田; 泰子濁川; 裕力名倉; 将徳伏見; 石井　章央; 勉南明; 絢子高木; 雅士鈴木; 浩也佐藤
Original assignee: セントラル硝子株式会社; 杏林製薬株式会社
Priority date: 2011-11-17
Filing date: 2012-11-13
Publication date: 2013-05-23
Also published as: JP2013126970A

Abstract

The present invention is a method for producing an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected form, comprising an amino group protection step for protecting amino groups of an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protected form, a dehydroxyfluorination step for reacting the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protected form obtained by the above-mentioned step with sulfuryl fluoride in the presence of an organic base, and a selective deprotection step for selective deprotection of the nitrobenzenesulfonyl protector groups of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protected form obtained by the above-mentioned step (where Cbz is a benzyloxycarbonyl group and Ns is a nitrobenzenesulfonyl group).

Description

Industrial production method of optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidines

The present invention relates to a method for producing optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidines.

Methods for producing optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidines are disclosed in Patent Documents 1 to 3. Among them, the method described in Patent Document 3 is an improved method based on an industrial production method.

On the other hand, Patent Document 4 discloses an alcohol based on a combination of sulfuryl fluoride (SO ₂ F ₂ ) and an organic base (performed in the presence of a “salt or complex comprising an organic base and hydrogen fluoride” as necessary). A class of dehydroxyfluorination reactions has been disclosed.

International Publication No. 2003/078439 JP 2005-239617 A International Publication No. 2007/102567 JP 2006-290870 A

Patent Document 3 discloses perfluoro-1-octanesulfonyl fluoride, which is relatively difficult to obtain on a large scale, and relatively expensive 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). It is necessary to use it. Further, DBU salt of perfluoro-1-octanesulfonic acid, which has been pointed out as environmentally toxic, is produced as a by-product in a quantitative manner, and its removal requires purification by column chromatography. Therefore, it was not an industrially easy manufacturing method.

On the other hand, in the dehydroxyfluorination reaction of amino alcohols according to Patent Document 4, it is important to select an amino protecting group (see JP 2009-227596 A and JP 2009-286779 A). Also in the similar reaction of Patent Document 3, it is disclosed that the yield of the target fluorinated compound is greatly influenced by the type of amino protecting group at the 3-cyclopropylaminomethyl moiety [high yield / benzyl group. (Examples 7 and 16) vs. Low yield / benzyloxycarbonyl group (Example 20), tert-butoxycarbonyl group (Example 22)].

Under such circumstances, it is necessary to find a suitable amino protecting group for producing optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidines in a high yield by an industrially easy method. Furthermore, if it is an amino protecting group capable of selective deprotection with respect to the 1-position benzyloxycarbonyl protecting group, it can be used as an intermediate for medical and agricultural chemicals.

As a result of intensive studies, the present inventors have shown that an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protector [Cbz represents a benzyloxycarbonyl group, and Ns represents a nitrobenzenesulfonyl group (the same applies hereinafter). It was found that an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protected product can be produced by reacting with a sulfuryl fluoride in the presence of an organic base (dehydroxyfluorination step). By selecting a nitrobenzenesulfonyl group as the amino protecting group at the 3-cyclopropylaminomethyl moiety, the desired fluorinated product can be obtained in high yield.

The optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protector, which is a raw material substrate, can be suitably converted from the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector as a precursor. The precursor has a hydroxyl group and an amino group in the molecule, but the amino group can be selectively protected. Furthermore, the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protector obtained in the dehydroxyfluorination step can selectively deprotect the nitrobenzenesulfonyl protecting group. Thus, a series of preparations from the precursor to selective deprotection is a preferred embodiment of the present invention.

Furthermore, it has also been found that the desired reaction proceeds satisfactorily by performing the dehydroxyfluorination step in the presence of a salt or complex comprising an organic base and hydrogen fluoride.

Further, the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protector and the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protector are extremely important intermediates in the production method of the present invention. .

That is, the present invention provides an industrial process for producing optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidines of the following [Invention 1] to [Invention 3].

[Invention 1]
General formula [1]:

[Wherein, Cbz represents a benzyloxycarbonyl group, and Ns represents a nitrobenzenesulfonyl group. ]
By reacting an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protected compound represented by the following formula with sulfuryl fluoride in the presence of an organic base:

[Wherein, Cbz and Ns are the same as those in the general formula [1]. ]
An optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protected product comprising a step of converting to an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protected product represented by (dehydroxyfluorination step). Production method.

[Invention 2]
General formula [3]:

[Wherein, Cbz represents a benzyloxycarbonyl group. ]
By protecting the amino group of the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protected group represented by the following general formula [1]:

[Wherein, Cbz is the same as in the general formula [3], and Ns represents a nitrobenzenesulfonyl group. ]
A step of converting to an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protected product represented by (amino group protecting step),
By reacting the protected optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs with sulfuryl fluoride in the presence of an organic base, the compound represented by the general formula [2]:

[Wherein, Cbz and Ns are the same as those in the general formula [1]. ]
A step (dehydroxyfluorination step) of converting to an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protectant represented by the above, and an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protector By selectively deprotecting the nitrobenzenesulfonyl protecting group, the general formula [4]:

[Wherein, Cbz is the same as the general formula [2]. ]
Production of an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected product comprising a step of obtaining an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected product represented by (selective deprotection step) Method.

[Invention 3]
3. The method according to claim 1 or 2, wherein the reaction with the sulfuryl fluoride in the dehydroxyfluorination step is carried out in the presence of a salt or complex comprising an organic base and hydrogen fluoride.

Sulfuryl fluoride used in the dehydroxyfluorination process of the present invention is widely used as a fumigant, and the fluorosulfuric acid produced as a by-product in terms of quantity is also less environmental impact, and its salts with organic bases can be easily washed with water. It can be removed by an after-treatment operation. In addition, the organic base used in the dehydroxyfluorination step of the present invention may be a relatively inexpensive one. Therefore, it is an industrially easy manufacturing method.

Further, as a suitable amino protecting group at the 3-cyclopropylaminomethyl moiety, the nitrobenzenesulfonyl protecting group found in the present invention is not disclosed at all in Patent Document 3, and the desired fluorinated product can be obtained in a high yield. In addition, selective deprotection to the 1-position benzyloxycarbonyl protecting group is possible.

Furthermore, the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector obtained in the selective deprotection step is derived from a salt with an inorganic acid such as hydrogen chloride and recrystallized and purified. Goods can be obtained.

Thus, the present invention is a useful manufacturing method that solves the problems of the prior art at once.

Incidentally, the present invention uses a compound in which the nitrobenzenesulfonyl group of the protected optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs is substituted with a benzyl group, a benzyloxycarbonyl group and a tert-butoxycarbonyl group, respectively, as a raw material substrate. Even when this production condition was applied, the yield of the desired fluorinated product was much lower than that of the present invention (nitrobenzenesulfonyl group).

Hereinafter, the present invention will be described in detail. The scope of the present invention is not limited to these descriptions, and other than the following examples, the scope of the present invention can be appropriately changed and implemented without departing from the spirit of the present invention. It should be noted that all publications cited in the present specification, for example, prior art documents, and publications, patent publications, and other patent documents are incorporated herein by reference.

The production method of Invention 2, which is a preferred embodiment of the present invention, includes three steps: “1. amino group protection step”, “2. dehydroxyfluorination step” and “3. selective deprotection step”. Invention 1 corresponds to “2. Dehydroxyfluorination step” of Invention 2, and Invention 3 corresponds to a preferred embodiment in “Dehydroxyfluorination step” of Invention 1 or 2.

Hereinafter, each manufacturing process will be described in detail.

1. Amino group protection step This step is carried out by protecting the amino group of the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector represented by the general formula [3] with a nitrobenzenesulfonyl group. In the protected form of an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs represented by the formula:

In the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protected body represented by the general formula [3], Cbz represents a benzyloxycarbonyl group.

The optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector represented by the general formula [3] can be similarly produced with reference to Patent Document 3.

The optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector represented by the general formula [3] may be its enantiomer (3R, 4S). The optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector represented by the general formula [3] is an inorganic acid such as hydrogen chloride, hydrogen bromide and sulfuric acid or oxalic acid, phthalic acid and paratoluenesulfonic acid, etc. It can also be used in the form of a salt with an organic acid. Accordingly, the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protected body represented by the general formula [3] in the claims is treated as including these enantiomers and salts.

Amino group protection process is a general method in organic synthesis [eg, Protective Groups Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc., The Chemical Society of Japan, 5th edition, Experimental Chemistry Course (Maruzen), etc.] This can be done by adopting Although the following method is mentioned as a specific example, Naturally it is not limited to this.

By reacting an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector represented by the general formula [3] with a nitrobenzenesulfonyl halide represented by the general formula [5] in the presence of a base, Conversion into a protected form of optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs represented by the formula [1] (specific example)

[Wherein the nitro group is substituted at the ortho, meta or para position, and X represents a halogen atom. ]

The nitro group of the nitrobenzenesulfonyl halide represented by the general formula [5] is substituted at the ortho, meta or para position. Of these, the ortho and para positions are preferred, and the ortho position is particularly preferred.

X in the nitrobenzenesulfonyl halide represented by the general formula [5] represents a halogen atom. The halogen atom is fluorine, chlorine, bromine or iodine. Of these, chlorine and bromine are preferable, and chlorine is particularly preferable.

Among the nitrobenzenesulfonyl halides represented by the general formula [5], ortho and para-nitrobenzenesulfonyl fluoride or ortho and para-nitrobenzenesulfonyl chloride are preferable, and ortho and para-nitrobenzenesulfonyl chloride are particularly preferable. Ortho and para-nitrobenzenesulfonyl chloride are commercially available and are readily available. Among these, ortho-nitrobenzenesulfonyl chloride is very preferable because it is cheaper and suitable for production on a large scale. In the present invention, ortho and para-nitrobenzenesulfonyl fluoride can also be suitably used.

The amount of the nitrobenzenesulfonyl halide represented by the general formula [5] is 0.7 mol or more with respect to 1 mol of the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector represented by the general formula [3]. It may be used, preferably 0.8 to 5 mol, particularly preferably 0.9 to 3 mol.

The base is an inorganic base such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide. , And triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3. Organic bases such as 0] non-5-ene and 1,8-diazabicyclo [5.4.0] undec-7-ene. Among them, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 2, 4,6-collidine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene and 1,8-diazabicyclo [5.4.0] undec-7-ene are preferred, Sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 4-dimethylaminopyridine and 1,8-diazabicyclo [5.4 .0] Undeca-7-D It is particularly preferred. These bases can be used alone or in combination.

The amount of the base used may be 0.35 mol or more with respect to 1 mol of the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector represented by the general formula [3], preferably 0.4 to 20 mol. 0.45 to 15 mol is particularly preferable. When the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector represented by the general formula [3] is used in the form of a salt with an inorganic acid or an organic acid, use of a base necessary for neutralizing the acid is used. It is convenient to add the amount in consideration and to carry out the neutralization of the acid and the protection of the amino group continuously as one reaction. The base used for acid neutralization is the same as the base described in this step.

Reaction solvents include aliphatic hydrocarbons such as n-hexane and n-heptane, aromatic hydrocarbons such as toluene and xylene, halogens such as methylene chloride and 1,2-dichloroethane, tetrahydrofuran and tert-butyl methyl ether Ethers such as ethyl acetate and esters such as ethyl acetate and n-butyl acetate, N, N-dimethylformamide, 1-methyl-2-pyrrolidinone, N, N-dimethylacetamide and 1,3-dimethyl-2-imidazolidinone Amides such as acetonitrile, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide, and water. Of these, n-heptane, toluene, methylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, acetonitrile, dimethyl sulfoxide and water are preferable. Toluene, methylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, acetonitrile And water are particularly preferred. These reaction solvents can be used alone or in combination. This step can also be carried out in a heterogeneous system or a two-phase system of “a reaction solvent immiscible with water” and water.

The reaction solvent may be used in an amount of 0.05 L (liter) or more per 1 mol of the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector represented by the general formula [3]. To 20 L is preferred, and 0.15 to 10 L is particularly preferred. This step can also be performed in a solvent-free mixture without using a reaction solvent.

The order of addition is not particularly limited, and an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector represented by the general formula [3] and a nitrobenzenesulfonyl halide represented by the general formula [5] are used as a reaction solvent. In addition, when the base is gradually added later, or when the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector and the base are added to the reaction solvent, the nitrobenzenesulfonyl halides and a predetermined amount of the remaining amount are added. Adding bases in portions can give good results.

The reaction temperature may be in the range of −80 to + 200 ° C., preferably −60 to + 150 ° C., particularly preferably −40 to + 100 ° C.

The reaction time may be within a range of 24 hours or less, and varies depending on the raw material substrate, the reactants, and the reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, liquid chromatography, nuclear magnetic resonance, It is preferable to set the end point when the decrease in the raw material substrate is hardly recognized.

In the post-treatment, by employing a general operation in organic synthesis, an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protector represented by the general formula [1] can be obtained. The crude product can be purified to a high purity by activated carbon treatment, recrystallization, column chromatography or the like, if necessary. In particular, a salt of an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector represented by the general formula [3] with an inorganic acid (for example, a hydrogen chloride salt or a hydrobromide salt) or a general formula [5] In some cases, halide ions derived from the nitrobenzenesulfonyl halides shown below can cause impurities as a by-product in the dehydroxyfluorination process (see JP 2010-163422 A). In such a case, it is effective to wash the organic layer containing the target product (including washing with an aqueous solution of an inorganic salt not containing halide ions such as sodium sulfate) or to remove halide ions using a short column or the like. Furthermore, when the unreacted nitrobenzenesulfonyl halide represented by the general formula [5] remains, the target compound and the organic layer containing the nitrobenzenesulfonyl halide are mixed with ammonia, methylamine, ethylamine, dimethylamine, diethylamine, pyrrolidine. A primary or secondary amine having 1 to 6 carbon atoms such as piperidine, an aqueous solution of ammonia or the amine, or a lower alcohol solution having 1 to 6 carbon atoms such as ammonia or the amine (for example, methanol solution of methylamine, ethylamine) Methanol solution, dimethylamine methanol solution, diethylamine methanol solution, methylamine ethanol solution, ethylamine ethanol solution, dimethylamine ethanol solution, diethylamine ethanol solution, pyrrolidine methanol It is effective to make it come into contact with an aqueous solution, an ethanol solution of pyrrolidine, etc., which is a preferred embodiment (the nitrobenzenesulfonyl halides can be aminolyzed or hydrolyzed to remove liberated halide ions to the aqueous layer. ).

The amount of ammonia or the primary or secondary amine used may be 0.1 mol or more, preferably 0.2 to 2000 mol, preferably 0.3 to 1000 mol, relative to 1 mol of unreacted nitrobenzenesulfonyl halides. Is particularly preferred.

2. Dehydroxyfluorination step This step is carried out by reacting the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protectant represented by the general formula [1] with sulfuryl fluoride in the presence of an organic base. This is a step of converting into an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protector represented by the formula [2].

In the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protected body represented by the general formula [1], Cbz is the same as in the general formula [3], and Ns represents a nitrobenzenesulfonyl group.

The optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protector represented by the general formula [1] may be its enantiomer (3S, 4S). Therefore, the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protector represented by the general formula [1] in the claims is treated as including this enantiomer.

The amount of sulfuryl fluoride used may be 0.7 mol or more with respect to 1 mol of the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protector represented by the general formula [1]. Is preferable, and 0.9 to 15 mol is particularly preferable.

The organic base is the same as the organic base described in “1. Amino group protection step”. However, it is not limited to these, The organic base generally used in organic synthesis can also be employ | adopted. Among them, triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, pyridine, 2,6-lutidine, 1,5-diazabicyclo [4.3.0] non-5-ene and 1,8-diazabicyclo [ 5.4.0] Undec-7-ene is preferred, with triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, pyridine and 2,6-lutidine being particularly preferred. These organic bases can be used alone or in combination.

The amount of the organic base used may be 0.7 mol or more with respect to 1 mol of the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protector represented by the general formula [1]. Preferably, 0.9 to 15 mol is particularly preferable.

In the dehydroxyfluorination step, the reaction of the protected optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs represented by the general formula [1] with sulfuryl fluoride is carried out by “from organic base and hydrogen fluoride. More preferably, it is carried out in the presence of a “salt or complex”.

Here, the organic base in the “salt or complex comprising an organic base and hydrogen fluoride” is the same as the organic base described in this step. The same applies to “preferred” and “particularly preferred organic base”. These organic bases of “a salt or complex comprising an organic base and hydrogen fluoride” can be used alone or in combination.

The molar ratio of the organic base to hydrogen fluoride in the “salt or complex comprising an organic base and hydrogen fluoride” may be used in the range of 100: 1 to 1: 100, preferably 50: 1 to 1:50, Particularly preferred is 25: 1 to 1:25. Commercially available from Aldrich (2009-2010 catalog) “complex consisting of 1 mol of triethylamine and 3 mol of hydrogen fluoride” or “from pyridine˜30% (˜10 mol%) and hydrogen fluoride˜70% (˜90 mol%) It is convenient to use "complex".

The amount used when the “salt or complex comprising an organic base and hydrogen fluoride” is used is 1 mol of the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protector represented by the general formula [1]. The fluoride ion (F ⁻ ) may be 0.05 mol or more, preferably 0.07 to 30 mol, particularly preferably 0.09 to 15 mol.

The reaction solvent is the same as the reaction solvent described in “1. Amino group protection step”. However, water is excluded. The same applies to “preferred” and “particularly preferred reaction solvent”. These reaction solvents can be used alone or in combination.

The reaction solvent may be used in an amount of 0.05 L or more with respect to 1 mol of the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protector represented by the general formula [1]. Preferably, 0.15 to 10 L is particularly preferable. This step can also be performed in a solvent-free mixture without using a reaction solvent.

The reaction temperature may be in the range of −50 to + 200 ° C., preferably −40 to + 150 ° C., particularly preferably −30 to + 100 ° C.

The reaction time may be within a range of 48 hours, and varies depending on the raw material substrate, the reactants, and the reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, liquid chromatography, and nuclear magnetic resonance. It is preferable to set the end point when the decrease in the raw material substrate is hardly recognized.

In the post-treatment, an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protector represented by the general formula [2] can be obtained by employing a general operation in organic synthesis. The crude product can be purified to a high purity by activated carbon treatment, recrystallization, column chromatography or the like, if necessary. Since this step proceeds by the S _N 2 reaction, the stereochemistry of the 4-position asymmetric carbon of the general formula [1] is reversed.

3. Selective deprotection step This step is carried out by selectively deprotecting the nitrobenzenesulfonyl protecting group of the protected optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs represented by the general formula [2]. This is a step for obtaining an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected product represented by [4].

Cbz and Ns in the protected optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs represented by the general formula [2] are the same as those in the general formula [1].

The optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protector represented by the general formula [2] may be its enantiomer (3S, 4R). Therefore, the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protector represented by the general formula [2] in the claims is treated as including this enantiomer.

The selective deprotection process is a common method in organic synthesis [for example, Protective Groups Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc., The Chemical Society of Japan, 5th edition, Experimental Chemistry Course (Maruzen), etc. ] Can be used. Although the following method is mentioned as a specific example, Naturally it is not limited to this.

By reacting the protected optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs represented by the general formula [2] with a thiol represented by the general formula [6] in the presence of a base, the general formula [2] 4] The optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected product represented by 4] is produced (specific example).

[Wherein, R represents an alkyl group, a substituted alkyl group, a phenyl group or a substituted phenyl group. ]

R in the thiols represented by the general formula [6] represents an alkyl group, a substituted alkyl group, a phenyl group or a substituted phenyl group. The alkyl group is a linear or branched chain or cyclic group (having 3 or more carbon atoms) having 1 to 12 carbon atoms. The substituted alkyl group and the substituted phenyl group each have a substituent in any number and in any combination on any carbon atom of the alkyl group and phenyl group. Such substituents are amino groups, hydroxyl groups, carboxyl groups and the like. Among these, an alkyl group having 1 to 8 carbon atoms, a 2-hydroxyethyl group, a carboxymethyl group and a phenyl group are preferable, and a phenyl group is particularly preferable. Thiophenol (R is a phenyl group) has high reactivity and is commercially available as an industrial chemical.

The amount of the thiol represented by the general formula [6] is 0.7 mol or more based on 1 mol of the protected optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs represented by the general formula [2]. It is preferably 0.8 to 20 mol, particularly preferably 0.9 to 15 mol.

The base can be selected from the same bases listed in “1. Amino group protection step”. Among these, an inorganic base is preferable, and potassium carbonate, cesium carbonate, and lithium hydroxide are particularly preferable. These bases can be used alone or in combination. In the deprotection of the nitrobenzenesulfonyl protecting group of the amino group, the organic base 1,8-diazabicyclo [5.4.0] undec-7-ene is frequently used as the base. However, in the selective deprotection step of the present invention, milder reaction conditions can be adopted when using an inorganic base, and it is selected with respect to the 1-position benzyloxycarbonyl protecting group in good yield without side reactions. Deprotection can be performed (a preferred embodiment of the present invention). Of course, the use of an organic base in this step is not limited.

The amount of the base used may be 0.35 mol or more with respect to 1 mol of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protector represented by the general formula [2], preferably 0.4 to 20 mol. 0.45 to 15 mol is particularly preferable.

The reaction solvent is the same as the reaction solvent described in “1. Amino group protection step”. Among them, n-heptane, toluene, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, 1-methyl-2-pyrrolidinone, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile and dimethyl Sulfoxides are preferred, with tetrahydrofuran, N, N-dimethylformamide, 1-methyl-2-pyrrolidinone, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile and dimethyl sulfoxide being particularly preferred.

The reaction solvent may be used in an amount of 0.05 L or more per 1 mol of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protector represented by the general formula [2]. Preferably, 0.15 to 10 L is particularly preferable. This step can also be performed in a solvent-free mixture without using a reaction solvent.

The reaction temperature may be in the range of −50 to + 100 ° C., preferably −40 to + 90 ° C., particularly preferably −30 to + 80 ° C.

The reaction time may be performed within 36 hours, and varies depending on the raw material substrate, the reactants, and the reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, liquid chromatography, nuclear magnetic resonance, It is preferable to set the end point when the decrease in the raw material substrate is hardly recognized.

In the post-treatment, an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector represented by the general formula [4] can be obtained by employing a general operation in organic synthesis. The crude product can be purified to a high purity by activated carbon treatment, recrystallization, column chromatography or the like, if necessary.

Cbz of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector represented by the general formula [4] is the same as the general formula [2].

The optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector represented by the general formula [4] may be its enantiomer (3R, 4R). Therefore, the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected body represented by the general formula [4] in the claims is treated as including these enantiomers and salts.

The optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector represented by the general formula [4] is an inorganic acid such as hydrogen chloride, hydrogen bromide and sulfuric acid or oxalic acid, phthalic acid and paratoluenesulfonic acid, etc. A high-purity product can be obtained by recrystallization and purification by inducing a salt with an organic acid (a preferred embodiment of the present invention).

EXAMPLES Embodiments of the present invention will be specifically described by way of examples, but the present invention is not limited to these examples.

[Example 1]
In a glass reaction vessel, the following formula:

25.0 g (76.5 mmol, 1.00 eq) of hydrogen chloride (HCl) salt of an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector represented by the following formula: Ortho with 125 mL (1.63 L / mol) of acetonitrile -Add 17.1 g (77.2 mmol, 1.01 eq) of nitrobenzenesulfonyl chloride, soak in a refrigerant bath at -10 ° C, gradually add 16.3 g (161 mmol, 2.10 eq) of triethylamine, and stir at the same temperature for 35 minutes did. The conversion rate of the reaction finished liquid was 100% by liquid chromatography analysis. The reaction-terminated liquid is diluted with 250 mL of toluene, washed with 125 mL of 5% aqueous sodium hydrogen carbonate solution, the recovered aqueous layer is extracted with 63.0 mL of toluene, and the combined organic layers are washed with 63.0 mL of water and washed with 10% sulfuric acid. The organic layer was washed with 63.0 mL of sodium aqueous solution, and the collected organic layer was concentrated under reduced pressure. The residue was dissolved in 125 mL of ethyl acetate and 125 mL of toluene, washed twice with 63.0 mL of 10% aqueous sodium sulfate solution, and concentrated under reduced pressure. formula:

40.1 g of an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protected product represented by the formula: The yield was quantitative (theoretical yield 36.4 g). ¹ H-NMR is shown below.
¹ H-NMR (reference material; Me ₄ Si, heavy solvent; CDCl ₃ ), δ ppm; 0.65 (m, 4H), 2.63 (m, 3H), 3.38 (m, 4H), 3 .75 (m, 2H), 4.30 (m, 1H), 5.13 (s, 2H), 7.63 (Ar, 9H).

In a pressure resistant reaction vessel made of stainless steel (SUS), the total amount of the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protector obtained above was 40.1 g (76.5 mmol, 1.00 eq), acetonitrile 75 0.0 mL (0.980 L / mol), 31.0 g (306 mmol, 4.00 eq) of triethylamine and 12.3 g (76.3 mmol, 0.997 eq) of triethylamine / hydrogen trifluoride were added, and immersed in a refrigerant bath at 0 ° C. 17.0 g (167 mmol, 2.18 eq) of sulfuryl fluoride was blown from the bomb and stirred at the same temperature for 4 hours. The conversion rate of the reaction finished liquid was 100% by liquid chromatography analysis. To the reaction solution, 230 mL of 10% potassium carbonate aqueous solution was added, extracted with 230 mL of ethyl acetate, the recovered aqueous layer was extracted with 75.0 mL of ethyl acetate, and the combined organic layers were washed with 90.0 mL of 2N hydrochloric acid, and 10% Wash with 3 times 75.0 mL of brine and concentrate under reduced pressure. Dissolve the residue in 230 mL of ethyl acetate, filter, concentrate under reduced pressure and azeotrope with 75.0 mL of acetonitrile to obtain the following formula:

As a result, 39.4 g of an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protected product represented by the formula: The yield was quantitative (theoretical yield 36.5 g). ¹ H-NMR and ¹⁹ F-NMR are shown below.
¹ H-NMR (reference material; Me ₄ Si, deuterated solvent; CDCl ₃ ), δ ppm; 0.70 (m, 4H), 2.51 (m, 1H), 2.75 (m, 1H), 3 .55 (m, 6H), 5.18 (m, 1H), 5.14 (s, 2H), 7.63 (Ar, 9H).
¹⁹ F-NMR (reference material; C ₆ F ₆ , heavy solvent; CDCl ₃ ), δ ppm; −30.97 (m, 1F).

In a glass reaction vessel, a total amount of 39.4 g (76.5 mmol, 1.00 eq) of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs obtained above, 150 mL of N, N-dimethylformamide. (1.96 L / mol) and 31.7 g (229 mmol, 2.99 eq) of potassium carbonate, soaked in a refrigerant bath at −5 ° C., and 21.8 g (198 mmol, 2.59 eq) of thiophenol were added. Stir for 3 hours 30 minutes. The conversion rate of the reaction finished liquid was 100% by liquid chromatography analysis. 600 mL of water was added to the reaction completed solution, extracted with 600 mL of ethyl acetate, the recovered aqueous layer was extracted with 150 mL of ethyl acetate, and the combined organic layers were washed twice with 75.0 mL of 10% brine, concentrated under reduced pressure, By azeotroping with 75.0 mL of ethyl acetate, the following formula:

As a result, 53.7 g of an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected product represented by the formula: The yield was quantitative (theoretical yield 22.4 g). The purity of liquid chromatography was 96.5% (except for the peak derived from the deprotected Ns group).

The total amount of optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz obtained above (53.7 g, 76.5 mmol) was dissolved in 230 mL of ethyl acetate, filtered, and immersed in a 0 ° C. refrigerant bath. Then, hydrogen chloride-methanol reagent (5-10%, manufactured by Tokyo Chemical Industry Co., Ltd.) was added until the pH reached 3 (62.0 mL), 690 mL of diisopropyl ether was gradually added, and the mixture was stirred at the same temperature for 1 hour to precipitate. The crystals thus obtained were filtered and dried under vacuum to obtain 24.3 g of a hydrogen chloride (HCl) salt of an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected product represented by the above formula. The total yield from “1. Amino group protection step” was 96%. Liquid chromatographic purity was 96.5%.

A total of 24.3 g of the hydrogen chloride (HCl) salt of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector obtained above was heated to 120 mL of methanol and 96.0 mL of isopropanol under heating (46 ° C. or lower). Dissolve, add 120 mL of diisopropyl ether, stir at 30 ° C. for 1 hour, add 96.0 mL of diisopropyl ether, stir at the same temperature for 30 minutes, 1 hour at 0 ° C., filter the precipitated crystals, and vacuum dry As a result, 21.3 g of hydrogen chloride (HCl) salt (recrystallized product) of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected product represented by the above formula was obtained. The recovery rate was 88%. Liquid chromatography purity was 98.4%. ¹ H-NMR and ¹⁹ F-NMR are shown below.
¹ H-NMR (reference material; Me ₄ Si, deuterated solvent; CDCl ₃ ), δ ppm; 0.84 (m, 2H), 1.24 (m, 2H), 2.57 (m, 1H), 3 .13 (m, 4H), 3.77 (m, 3H), 5.12 (m, 2H), 5.48 (m, 1H), 7.32 (Ar, 5H), 9.86 (br, 2H).
¹⁹ F-NMR (reference material; C ₆ F ₆ , deuterated solvent; CDCl ₃ ), δ ppm; −31.57 (m, 1F).

[Example 2]
In a glass reaction vessel, the following formula:

150 g (459 mmol, 1.00 eq) of a hydrogen chloride (HCl) salt of an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector represented by the formula: 675 mL (1.47 L / mol) of acetonitrile and ortho-nitrobenzenesulfonyl chloride 103 g (465 mmol, 1.01 eq) was added, immersed in a 0 ° C. refrigerant bath, 98.2 g (970 mmol, 2.11 eq) of triethylamine was gradually added, and the mixture was stirred at the same temperature for 3 hours. The conversion rate of the reaction finished liquid was 99% according to liquid chromatography analysis. The reaction-terminated liquid is diluted with 1.35 L of toluene, washed with 675 mL of 5% aqueous sodium hydrogen carbonate solution, the recovered aqueous layer is extracted with 300 mL of toluene, the combined organic layers are washed with 300 mL of water, and 10% aqueous sodium sulfate solution Wash with 300 mL, concentrate the recovered organic layer under reduced pressure, and azeotrope with 300 mL of ethyl acetate and 300 mL of toluene to obtain the following formula:

As a result, 237 g of an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protected product represented by the formula: The yield was quantitative (theoretical yield 218 g).

In a pressure resistant reaction vessel made of stainless steel (SUS), a total of 237 g (459 mmol, 1.00 eq) of the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protector obtained above, 460 mL of ethyl acetate (1. 00L / mol), 149 g (1.47 mol, 3.20 eq) of triethylamine and 74.0 g (459 mmol, 1.00 eq) of triethylamine / hydrogen trifluoride were added, and immersed in a refrigerant bath at 0 ° C., 60.0 g of sulfuryl fluoride. (588 mmol, 1.28 eq) was blown from the bomb and stirred at the same temperature for 3 hours and at room temperature for 1 hour. The conversion rate of the reaction finished liquid was 100% by liquid chromatography analysis. 1.15 L of 10% aqueous potassium carbonate solution was added to the reaction completed solution, extracted with 920 mL of ethyl acetate, the recovered aqueous layer was extracted with 150 mL of ethyl acetate, and the recovered organic layers were combined and washed with 460 mL of 2N hydrochloric acid (containing 5% salt). And washed with 460 mL of 5% aqueous sodium hydrogen carbonate solution (containing 5% sodium chloride), concentrated under reduced pressure, and azeotroped with 300 mL of ethyl acetate and 300 mL of toluene to obtain the following formula:

As a result, 234 g of an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protected product represented by the formula: The yield was quantitative (theoretical yield 219 g).

In a glass reaction vessel, a total of 234 g (459 mmol, 1.00 eq) of the protected optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs obtained above, 690 mL (1.50 L) of N, N-dimethylformamide. / Mol) and 190 g (1.37 mol, 2.98 eq) of potassium carbonate were added, immersed in a refrigerant bath at 0 ° C., 142 g (1.29 mol, 2.81 eq) of thiophenol was added, and the mixture was stirred at the same temperature for 4 hours. The conversion rate of the reaction finished liquid was 100% by liquid chromatography analysis. 1.73 L of water was added to the reaction completed solution, extracted with 1.38 L of ethyl acetate, the recovered aqueous layer was extracted with 460 mL of ethyl acetate, and the combined organic layers were washed twice with 460 mL of 10% brine and concentrated under reduced pressure. And azeotropically with 300 mL of ethyl acetate and 300 mL of toluene, the following formula:

308 g of an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected product represented by The yield was quantitative (theoretical yield 134 g). The purity of the liquid chromatography was 95.2% (except for the peak derived from the deprotected Ns group).

A total of 308 g (459 mmol) of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector obtained above was dissolved in 1.37 L of ethyl acetate, filtered, immersed in a 0 ° C. refrigerant bath, pH Hydrogen chloride-methanol reagent (5-10%, manufactured by Tokyo Kasei Kogyo Co., Ltd.) was added until it became 3, and 4.11 L of n-heptane was gradually added, followed by stirring at the same temperature for 1 hour to precipitate. The crystals are filtered, washed with 200 mL of n-heptane three times, and dried under vacuum to obtain a hydrogen chloride (HCl) salt of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector represented by the above formula. 137 g was obtained. The total yield from “1. Amino group protection step” was 91%. Liquid chromatography purity was 95.6%.

A total of 137 g of the hydrogen chloride (HCl) salt of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector obtained above was dissolved in 680 mL of methanol and 550 mL of isopropanol under heating (50 ° C. or lower), and diisopropyl Add 680 mL of ether, stir at 35 ° C. for 2 hours, add 550 mL of diisopropyl ether, stir for 1 hour at the same temperature and 1 hour at 0 ° C., filter the precipitated crystals, wash with 200 mL of diisopropyl ether three times, and vacuum By drying, 127 g of a hydrogen chloride (HCl) salt (recrystallized product) of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected product represented by the above formula was obtained. The recovery rate was 93%. Liquid chromatography purity was 98.5%.

[Example 3]
In a glass reaction vessel, the following formula:

10.0 g (30.6 mmol, 1.00 eq) of hydrogen chloride (HCl) salt of an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector represented by the following: 45.0 mL (1.47 L / mol) of ethyl acetate ) And 34.0 g of a 15% aqueous potassium carbonate solution (potassium carbonate 36.9 mmol, 1.21 eq), soaked in a 0 ° C. refrigerant bath, and 6.87 g (31.0 mmol, 1.01 eq) of ortho-nitrobenzenesulfonyl chloride. 25.0 g of a 15% aqueous potassium carbonate solution (27.1 mmol of potassium carbonate, 0.886 eq) was added in 5 portions, followed by stirring at the same temperature for 4 hours. The conversion rate of the reaction finished liquid was 99% according to liquid chromatography analysis. The reaction-terminated liquid is diluted with 15.0 mL of ethyl acetate, separated, and the recovered aqueous layer is extracted with 15.0 mL of ethyl acetate. The recovered organic layers are combined and washed twice with 10.0 mL of 5% aqueous sodium sulfate solution. The organic layer was washed with 10.0 mL of a 10% aqueous sodium sulfate solution, the collected organic layer was concentrated under reduced pressure, and azeotroped twice with 10.0 mL of ethyl acetate and 10.0 mL of toluene to obtain the following formula:

An optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protected product represented by the following formula was obtained.

In a pressure resistant reaction vessel made of stainless steel (SUS), the total amount of the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protector obtained above (30.6 mmol, 1.00 eq), ethyl acetate 30.0 mL (0.980 L / mol), 9.90 g (97.8 mmol, 3.20 eq) of triethylamine and 4.93 g (30.6 mmol, 1.00 eq) of triethylamine / hydrogen trifluoride were added and immersed in a refrigerant bath at 0 ° C. Then, an excessive amount of sulfuryl fluoride was blown from the cylinder and stirred at the same temperature for 4 hours. The conversion rate of the reaction finished liquid was 99% according to liquid chromatography analysis. 75.0 mL of 10% aqueous potassium carbonate solution was added to the reaction completed solution, extracted with 30.0 mL of ethyl acetate, the recovered aqueous layer was extracted with 15.0 mL of ethyl acetate, and the recovered organic layers were combined and 2N hydrochloric acid (containing 5% sodium chloride). ) Washed with 30.0 mL, washed with 30.0 mL of 5% aqueous sodium bicarbonate solution (containing 5% sodium chloride), concentrated under reduced pressure, and azeotroped with ethyl acetate to give the following formula:

19.5 g of an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protected product represented by the formula: The yield was quantitative (theoretical yield 14.6 g).

In a glass reaction vessel, a total amount of 19.5 g (30.6 mmol, 1.00 eq) of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs obtained above, N, N-dimethylformamide 45 0.0 mL (1.47 L / mol) and 13.8 g (99.8 mmol, 3.26 eq) of potassium carbonate were added, and immersed in a refrigerant bath at 0 ° C., 9.44 g (85.7 mmol, 2.80 eq) of thiophenol was added. In addition, the mixture was stirred at the same temperature for 3 hours. The conversion rate of the reaction finished liquid was 100% by liquid chromatography analysis. 113 mL of water was added to the reaction completed solution, extracted with 90.0 mL of ethyl acetate, the recovered aqueous layer was extracted with 45.0 mL of ethyl acetate, and the recovered organic layers were combined and washed twice with 45.0 mL of 5% brine, By concentrating under reduced pressure and azeotroping with 10.0 mL of ethyl acetate and 10.0 mL of toluene, the following formula:

An optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected product represented by the following formula was obtained.

The total amount (30.6 mmol) of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz obtained above was dissolved in 60.0 mL of ethyl acetate and 20.0 mL of n-heptane, and a refrigerant at 0 ° C. Immerse in a bath and add hydrogen chloride-methanol reagent (5-10%, manufactured by Tokyo Chemical Industry Co., Ltd.) until the pH is 3 (25.0 mL), gradually add 160 mL of n-heptane, and continue at the same temperature for 1 hour. The mixture was stirred and the precipitated crystals were filtered and dried under vacuum to obtain 8.85 g of a hydrogen chloride (HCl) salt of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector represented by the above formula. . The total yield from “1. Amino group protection step” was 88%. Liquid chromatography purity was 96.3%.

A total of 8.85 g of the hydrogen chloride (HCl) salt of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector obtained above was heated to 26.5 mL of methanol and 17.7 mL of ethyl acetate (50 ° C. 3) mL of n-heptane was added and stirred at 35 ° C. for 2 hours, 17.7 mL of n-heptane was added, and the mixture was stirred at the same temperature for 1 hour and at 0 ° C. for 1 hour. By filtration and vacuum drying, 7.65 g of a hydrogen chloride (HCl) salt (recrystallized product) of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected product represented by the above formula was obtained. The recovery rate was 86%. Liquid chromatography purity was 99.4%.

[Example 4]
In a glass reaction vessel, the following formula:

10.0 g (30.6 mmol, 1.00 eq) of hydrogen chloride (HCl) salt of the protected optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz represented by 45.0 mL (1.47 L / mol) of acetonitrile And ortho-nitrobenzenesulfonyl chloride 6.85 g (30.9 mmol, 1.01 eq) were added, immersed in a refrigerant bath at 0 ° C., and triethylamine 6.50 g (64.2 mmol, 2.10 eq) was gradually added at the same temperature. Stir for 2 hours. The conversion rate of the reaction finished liquid was 100% by liquid chromatography analysis. The reaction-terminated liquid is diluted with 90.0 mL of toluene, washed with 45.0 mL of 5% aqueous sodium hydrogen carbonate solution, the recovered aqueous layer is extracted with 20.0 mL of toluene, and the recovered organic layers are combined and 10.0 mL of 3% aqueous ammonia. By washing with 10.0 mL of water, washing twice with 20.0 mL of 10% aqueous sodium sulfate, and concentrating the recovered organic layer under reduced pressure and azeotroping with ethyl acetate and toluene. Following formula:

An optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protected product represented by the following formula was obtained. No ortho-nitrobenzenesulfonyl chloride was detected by liquid chromatography analysis.

In a pressure resistant reaction vessel made of stainless steel (SUS), the total amount of the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protector obtained above (30.6 mmol, 1.00 eq), ethyl acetate 30.0 mL (0.980 L / mol), 9.90 g (97.8 mmol, 3.20 eq) of triethylamine and 4.93 g (30.6 mmol, 1.00 eq) of triethylamine / hydrogen trifluoride were added and immersed in a refrigerant bath at 0 ° C. Then, an excessive amount of sulfuryl fluoride was blown from the bomb and stirred at the same temperature for 3 hours and at room temperature for 1 hour. The conversion rate of the reaction finished liquid was 100% by liquid chromatography analysis. 75.0 mL of 10% aqueous potassium carbonate solution was added to the reaction completed solution, extracted with 30.0 mL of ethyl acetate, the recovered aqueous layer was extracted with 15.0 mL of ethyl acetate, and the recovered organic layers were combined and 2N hydrochloric acid (containing 5% sodium chloride). ) Washed with 30.0 mL, washed with 30.0 mL of 5% aqueous sodium bicarbonate solution (containing 5% sodium chloride), concentrated under reduced pressure, and azeotroped with ethyl acetate to give the following formula:

An optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protected product represented by the following formula was obtained.

In a glass reaction vessel, the total amount of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protector obtained above (30.6 mmol, 1.00 eq), 45.0 mL of N, N-dimethylformamide ( 1.47 L / mol) and 12.7 g (91.9 mmol, 3.00 eq) of potassium carbonate were added, soaked in a refrigerant bath at 0 ° C., and 9.44 g (85.7 mmol, 2.80 eq) of thiophenol was added. Stir at temperature for 4 hours. The conversion rate of the reaction finished liquid was 100% by liquid chromatography analysis. To the reaction solution, 113 mL of water was added, extracted with 90.0 mL of ethyl acetate, the recovered aqueous layer was extracted with 45.0 mL of ethyl acetate, and the recovered organic layers were combined and washed twice with 30.0 mL of 10% brine, By concentration under reduced pressure and vacuum drying, the following formula:

The total amount of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector obtained above (30.6 mmol) was dissolved in 90.0 mL of ethyl acetate and 270 mL of n-heptane, and placed in a 0 ° C. refrigerant bath. Immerse and add hydrogen chloride-methanol reagent (5-10%, manufactured by Tokyo Chemical Industry Co., Ltd.) until the pH is 3 (25.0 mL), stir at the same temperature for 1 hour, filter the precipitated crystals, and vacuum By drying, 8.89 g of hydrogen chloride (HCl) salt of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected product represented by the above formula was obtained. The total yield from “1. Amino group protection step” was 88%. The liquid chromatography purity was 96.7%.

8.89 g of the total amount of hydrogen chloride (HCl) salt of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector obtained above was added to methanol (5 mL / g) -isopropanol (4 mL / g) -diisopropyl ether ( By recrystallization from 9 mL / g), 8.06 g of hydrogen chloride (HCl) salt (recrystallized product) of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector represented by the above formula was obtained. . The recovery rate was 91%. Liquid chromatography purity was 98.4%.

A total of 8.06 g of the hydrogen chloride (HCl) salt (recrystallized product) of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector obtained above was added to methanol (5 mL / g) -isopropanol (4 mL / g). ) -Diisopropyl ether (9 mL / g) to recrystallize the hydrogen chloride (HCl) salt (re-crystal product) of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector represented by the above formula. 7.54 g was obtained. The recovery rate was 94%. The liquid chromatography purity was 99.6%.

[Example 5]
The reaction was carried out in the same manner as in Example 4 except that washing with 10.0 mL of 3% aqueous ammonia was stirred and contacted with 0.5 mL of 40% methylamine / methanol solution for 30 minutes. As a result, a hydrogen chloride (HCl) salt (recrystallized product) of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector represented by the above formula was obtained in the same yield and recovery rate.

[Example 6]
In a glass reaction vessel, the following formula:

50.0 g (153 mmol, 1.00 eq) of hydrogen chloride (HCl) salt of an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protector represented by formula (150), ethyl acetate 150 mL, 15% aqueous potassium carbonate solution 155 g (168 mmol, 1.1 eq), soaked in a 0 ° C refrigerant bath, and 34.2 g (154 mmol, 1.01 eq) ortho-nitrobenzenesulfonyl chloride and 141 g (153 mmol, 1.0 eq) 15% aqueous potassium carbonate solution were divided into 5 portions. And stirred at the same temperature for 4 hours. The conversion rate of the reaction finished liquid was 100% by liquid chromatography analysis. The reaction end solution was diluted with 100 mL of toluene, and extracted with 50 mL of ethyl acetate. The recovered aqueous layer was extracted with 25 mL of toluene and 25 mL of ethyl acetate, and the recovered organic layers were combined and washed with 50 mL of 10% aqueous sodium sulfate. After cooling the organic layer to 15 to 20 ° C. and adding 5 mL of 40% methylamine / methanol solution to react for 2 hours, the organic layer was prepared from ion-exchanged water and high-purity sodium sulfate (for example, ACS grade manufactured by Aldrich). Washed three times with 50 mL of 10% aqueous sodium sulfate. The recovered organic layer was concentrated under reduced pressure and azeotroped with ethyl acetate and toluene to give the following formula:

Thus, 87.2 g of an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protected product represented by the formula: No ortho-nitrobenzenesulfonyl chloride was detected by liquid chromatography analysis.

In a pressure resistant reaction vessel made of stainless steel (SUS), the total amount of the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protector obtained above (referred to as 153 mmol, 1.00 eq), 153 mL of ethyl acetate (1.0 L) / Mol) and 76.4 g (753 mmol, 4.9 eq) of triethylamine were added and immersed in a −10 ° C. refrigerant bath. Anhydrous hydrogen fluoride (11.4 g, 570 mmol, 3.7 eq) was blown from the bomb, then immersed in a 0 ° C. refrigerant bath, and an excess amount of sulfuryl fluoride was blown from the bomb. The same temperature was maintained for 3 hours at 20 to 25 ° C. For 1 hour. The conversion rate of the reaction finished liquid was 100% by liquid chromatography analysis. To the reaction solution, 375 mL of 10% aqueous potassium carbonate solution was added, extracted with 150 mL of ethyl acetate, and the recovered aqueous layer was extracted with 75 mL of ethyl acetate. The collected organic layers were combined, washed with 125 mL of 2N hydrochloric acid (containing 5% sodium chloride), washed with 100 mL of 5% aqueous sodium hydrogen carbonate solution (containing 5% sodium chloride), concentrated under reduced pressure, and azeotroped with ethyl acetate to obtain the following. formula:

As a result, 85.8 g of an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protected product represented by the formula:

In a glass reaction vessel, the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protected substance obtained above (76.9 g, 137 mmol, 1.00 eq), N, N-dimethylformamide (170 mL) 8 mol / L) and 57.0 g (412 mmol, 3.00 eq) of potassium carbonate, soak in a 0 ° C. refrigerant bath, add 42.4 g (385 mmol, 2.80 eq) of thiophenol, and heat to 40 ° C. Stir at temperature for 6 hours. The conversion rate of the reaction finished liquid was 100% by liquid chromatography analysis. The reaction-terminated liquid was cooled to room temperature, 506 mL of water was added, and the mixture was extracted with 203 mL of ethyl acetate. The recovered aqueous layer was extracted with 102 mL of ethyl acetate, and the recovered organic layers were combined, washed twice with 137 mL of 10% aqueous sodium sulfate, and back-extracted with 180 mL of 1N hydrochloric acid and 45 mL of 0.1N hydrochloric acid. The recovered aqueous layers were combined, washed with 45 mL of toluene, and 137 mL of 20% aqueous potassium carbonate was added, followed by extraction with 137 mL of ethyl acetate. The recovered aqueous layer was extracted with 69 mL of ethyl acetate, and the combined organic layers were combined, washed with 45 mL of 10% aqueous sodium sulfate, concentrated under reduced pressure, and vacuum dried to obtain the following formula:

As a result, 38.1 g of an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected product represented by the formula (1) was obtained.

The total amount of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector obtained above (to 137 mmol) was dissolved in 270 mL of ethyl acetate, immersed in a 0 ° C. refrigerant bath, and chlorinated until the pH reached 3. Hydrogen-methanol reagent (5-10%, manufactured by Tokyo Chemical Industry Co., Ltd.) was added (119 mL), and 450 mL of heptane was further added. The mixture was stirred at the same temperature for 1 hour, and the precipitated crystals were filtered and dried under vacuum to obtain a hydrogen chloride (HCl) salt of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected body represented by the above formula. 36.4 g was obtained. The total yield from “1. Amino group protection step” was 81%. Liquid chromatographic purity was 99.00%.

The total amount of hydrogen chloride (HCl) salt of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector obtained above was added to methanol (3 mL / g) -ethyl acetate (5 mL / g) -heptane (5 mL / g). 33.3 g of a hydrogen chloride (HCl) salt (recrystallized product) of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protected product represented by the above formula was obtained. The recovery rate was 91%. Liquid chromatography purity was 99.35%.

The optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidines targeted in the present invention can be used as intermediates for medicines and agrochemicals.

Claims

General formula [1]:

[Wherein, Cbz represents a benzyloxycarbonyl group, and Ns represents a nitrobenzenesulfonyl group. ]
By reacting an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protected compound represented by the following formula with sulfuryl fluoride in the presence of an organic base:

[Wherein, Cbz and Ns are the same as those in the general formula [1]. ]
A process for producing an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protected product, which comprises the step of converting to an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protected product represented by the formula:
General formula [3]:

[Wherein, Cbz represents a benzyloxycarbonyl group. ]
By protecting the amino group of the optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine Cbz protected group represented by the following general formula [1]:

[Wherein, Cbz is the same as in the general formula [3], and Ns represents a nitrobenzenesulfonyl group. ]
A step of converting to an optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs protectant represented by:
By reacting the protected optically active 3-cyclopropylaminomethyl-4-hydroxypyrrolidine CbzNs with sulfuryl fluoride in the presence of an organic base, the compound represented by the general formula [2]:

[Wherein, Cbz and Ns are the same as those in the general formula [1]. ]
A step of converting to an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protectant represented by formula (1) and a nitrobenzenesulfonyl protecting group of the optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine CbzNs protectant selectively By deprotecting to general formula [4]:

[Wherein, Cbz is the same as the general formula [2]. ]
A process for producing an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector comprising the step of obtaining an optically active 3-cyclopropylaminomethyl-4-fluoropyrrolidine Cbz protector represented by the formula:
The method according to claim 1 or 2, wherein the reaction with the sulfuryl fluoride is carried out in the presence of a salt or complex comprising an organic base and hydrogen fluoride.