WO2011062139A1 - Method for manufacturing optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol - Google Patents

Abstract

Provided is a three-step method for manufacturing optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol. The provided method can dramatically reduce the amount of a palladium catalyst used and can complete the reaction in one cycle, thereby reducing manufacturing costs and simplifying the procedure. Furthermore, the final target substance is crystallized and purified through recrystallization, yielding a high-purity result. Also provided is optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester, a novel substance which is a key intermediate in the provided manufacturing method.

Description

Process for producing optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol

The present invention relates to a process for producing optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol important as a pharmaceutical intermediate.

Optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol is important as a pharmaceutical intermediate, and Patent Documents 1 and 2 disclose a method for producing the compound (see Scheme 1).

[In the formula, Bn, Me, Boc, *, THF, Pd (OH) ₂ / C, EtOH, (Boc) ₂ O and Aqueous dioxane are benzyl group, methyl group, tert-butoxycarbonyl group, asymmetric carbon, respectively. , Tetrahydrofuran, palladium hydroxide supported on carbon, ethanol, di-t-butyl dicarbonate, dioxane aqueous solution. ]

Special table 2003-516346 gazette Special table 2008-503501 gazette

The conventional method for producing optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol has the following problems.

In Patent Documents 1 and 2, debenzylation in the second step is difficult to be industrially employed. In order to complete the reaction, it was necessary to replace the palladium catalyst with a new one when hydrogen gas absorption was no longer observed, and the same reaction had to be repeated many times, and the operation was complicated. For example, it is necessary to repeat the same reaction twice in Example I-7 of Patent Document 1 and 3 times in Example I-13, resulting in an increase in the total amount of expensive palladium catalyst used (Example I). 7; 6.5 mol%, Example I IV 13; 7.6 mol%). In Patent Document 2, the reaction is completed once, but the amount of the palladium catalyst used is remarkably large [Example 18 (Step D: Deprotection); 24.0 mol%], and the production cost is high.

In addition, since optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol, which is the final target, is a high boiling oily substance, a purification method that can be easily carried out even on a large scale such as distillation or recrystallization is used. Therefore, it was difficult to industrially produce a high-purity product required as a pharmaceutical intermediate. Patent Document 2 discloses that “a pure product was obtained as a light brown oil” regarding the color tone and physical properties of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol. It was very different from the high-purity product (white crystals) of the compound obtained in 1.

Thus, there is a strong demand for an industrial production method of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol that is simple in operation, low in production cost, and capable of obtaining a high-purity product. It was.

Therefore, an object of the present invention is to solve the above-mentioned problems of the prior art and to provide an industrial production method of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol.

In view of the above problems, the present inventors reproduced the phenomenon in which dedibenzylation in the second step of Scheme 1 was difficult to complete in Reference Example 1, and found that optically active 3-dibenzylamino-2-fluoro-1- Although the conversion from propanol (dibenzyl compound) to optically active 3-benzylamino-2-fluoro-1-propanol (monobenzyl compound) proceeds satisfactorily, the optically active 3-amino-2 which is the target product from the monobenzyl compound. The conversion to -fluoro-1-propanol was found to be very slow. From this result, it is presumed that a bidentate compound having an amino group (secondary or primary) and a hydroxyl group simultaneously may act as a catalyst poison of the palladium catalyst.

Therefore, as a result of intensive studies on a production method that does not go through such a bidentate compound, the present inventors have achieved very good dedibenzylation simply by changing the order of the reaction steps using the same starting materials. It has been found that optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol can be produced industrially (see Scheme 2). As a key intermediate in the production of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol, a novel optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester is industrially used. It was also found that it can be manufactured.

[Wherein, R and Pd represent an alkyl group having 1 to 6 carbon atoms and a palladium catalyst, respectively. ]

By performing dedibenzylation in the first step, the amount of palladium catalyst used can be remarkably reduced (1 mol% or less), and the reaction can be completed in one time. It has also been found that the dedibenzylation in the first step proceeds very smoothly by adding an acid as an additive.

In addition, a highly pure product of the compound can be obtained by deriving the optically active 3-amino-2-fluoropropionic acid ester obtained by dedibenzylation in the first step into a salt with an acid and carrying out salt purification. The optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol finally obtained by subjecting this high purity product to tert-butoxycarbonylation in the second step and hydride reduction in the third step It was found that a high purity product of the final target product can be obtained by recrystallization purification. The reason why the optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol of the final product, which has been conventionally considered as an oily substance, is crystallized is because of the optically active 3-amino-2-fluoropropionic acid ester. In addition to the purification by salt purification, di-t-butyl dicarbonate used in tert-butoxycarbonylation does not remain at all in the final product and does not lower the purity. Subsequent to tert-butoxycarbonylation in the second step followed by hydride reduction in the third step, even if unreacted di-t-butyl dicarbonate remains in the second step, it is completely removed under the reaction conditions of the third step. (Since the production method of Scheme 1 performs tert-butoxycarbonylation in the final step, such an effect cannot be expected). Therefore, the order of the reaction steps is extremely important.

Furthermore, the tert-butoxycarbonylation in the second step was found to proceed very smoothly by adding a base as an additive.

The final target optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol obtained as a crystal has a melting point as low as 39 ° C. and is not necessarily a desirable physical property for recrystallization purification. It has also been found that a high-purity product can be recovered with good yield by using it.

Initially, various side reactions were expected in the production method shown in Scheme 2. For example, lactamization or (poly) amidation of optically active 3-amino-2-fluoropropionic acid ester obtained in the first step, optically active 3-tert-butoxycarbonylamino-2-fluoropropion obtained in the second step Racemization of acid esters and dehydrofluorination of 3-tert-butoxycarbonylaminoacrylic acid esters (derived from high acidity of α-position and β-position protons by introduction of electron-withdrawing amino protecting group) Reduction of optical purity of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol obtained in the third step (hydride reduction conditions for optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester) Racemization below) and the like. However, it has also been clarified that these side reactions hardly occur by adopting the reaction conditions disclosed in the present invention.

That is, the present invention includes [Invention 1] to [Invention 5], an industrial production method of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol, and a key intermediate in the production method As a novel substance, an optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester is provided.

[Invention 1]
The optically active 3-dibenzylamino-2-fluoropropionic acid ester represented by the general formula [1] is dedibenzylated with hydrogen gas (H ₂ ) in the presence of a palladium catalyst, and represented by the general formula [2]. A first step of converting to an optically active 3-amino-2-fluoropropionic acid ester, and an ester represented by the general formula [2] with tert-butoxycarbonyl di-t-butyl dicarbonate [(Boc) ₂ O] A second step of converting to an optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester represented by the general formula [3] by converting the ester compound represented by the general formula [3] to borohydride lithium light represented by (LiBH ₄₎ or sodium borohydride and a third step of hydride reduction with (NaBH _4), the general formula [4] Production method of the active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol.

[Wherein, R represents an alkyl group having 1 to 6 carbon atoms, Bn represents a benzyl group, Boc represents a tert-butoxycarbonyl group, and * represents an asymmetric carbon. ]

[Invention 2]
2. The production method according to claim 1, wherein the dedibenzylation in the first step is performed by adding an acid as an additive, and further the tert-butoxycarbonylation in the second step is performed by adding a base as an additive.

[Invention 3]
The optically active 3-tert-2-butoxycarbonylamino-2 obtained in the third step is subjected to salt purification by derivatizing the optically active 3-amino-2-fluoropropionic acid ester obtained in the first step into a salt with an acid. The production method according to invention 1 or 2, characterized in that recrystallization purification of fluoro-1-propanol is performed.

[Invention 4]
The recrystallization solvent of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol obtained in the third step is an aliphatic hydrocarbon type, an aromatic hydrocarbon type or a mixed solvent thereof. The manufacturing method according to claim 3.

[Invention 5]
An optically active 3-tert-butoxycarbonylamino-2-fluoropropionate represented by the general formula [3].

[Wherein, R represents an alkyl group having 1 to 6 carbon atoms, Boc represents a tert-butoxycarbonyl group, and * represents an asymmetric carbon. ]

In the production method of the present invention, since the debenzylation is performed in the first step, the amount of the palladium catalyst used can be remarkably reduced and the reaction can be completed at one time, so that the production cost is low. In addition to simple operation, the final product is crystallized and recrystallized to obtain a high-purity product. Therefore, according to the present invention, all the problems of the prior art can be solved, and optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol can be produced industrially advantageously. The present invention also provides optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester as a key intermediate in the production of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol. it can.

Hereinafter, the production method of the optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol of the present invention will be described in detail.

In the production method of the present invention, the optically active 3-dibenzylamino-2-fluoropropionic acid ester represented by the general formula [1] is dedibenzylated with hydrogen gas in the presence of a palladium catalyst. A first step of converting to an optically active 3-amino-2-fluoropropionic acid ester represented by formula (1) and tert-butoxycarbonyl (Boc) conversion of the ester represented by the general formula [2] with di-t-butyl dicarbonate Thereby converting the optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester represented by the general formula [3] into a lithium borohydride, and converting the ester compound represented by the general formula [3] into lithium borohydride. Alternatively, an optically active 3-tert-butoxycal represented by the general formula [4] by hydride reduction with sodium borohydride And a third step of converting the Niruamino-2-fluoro-1-propanol.

First, the dedibenzylation in the first step will be described in detail.

R of the optically active 3-dibenzylamino-2-fluoropropionic acid ester [1] represents an alkyl group having 1 to 6 carbon atoms. The alkyl group can be linear or branched, or cyclic (when the number of carbon atoms is 3 or more). Of these, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an n-pentyl group and an n-hexyl group are preferable, and a methyl group, an ethyl group, an n-propyl group and an isopropyl group are particularly preferable.

Bn in the optically active 3-dibenzylamino-2-fluoropropionic acid ester [1] represents a benzyl group.

* In the optically active 3-dibenzylamino-2-fluoropropionic acid ester [1] represents an asymmetric carbon, the absolute configuration can be R-form or S-form, and the optical purity is 80% ee (enantiomeric excess Rate) or higher, 90% ee or higher is preferable, and 95% ee or higher is particularly preferable.

Optically active 3-dibenzylamino-2-fluoropropionic acid ester [1] is disclosed in Journal of America, American Chemical, Society (USA), 1982, Vol. 104, p. 5836-5837, International Publication No. 2006/038872 pamphlet, International Publication No. 2009/133789 pamphlet, and the like, can be similarly produced.

Palladium catalysts include palladium black, palladium sponge, palladium / activated carbon, palladium / alumina, palladium / calcium carbonate, palladium / strontium carbonate, palladium / barium sulfate, palladium hydroxide / activated carbon, palladium hydroxide / alumina, palladium acetate, chloride. Palladium etc. are mentioned. Among these, palladium / activated carbon, palladium / alumina, palladium hydroxide / activated carbon and palladium hydroxide / alumina are preferable, and palladium / activated carbon and palladium hydroxide / activated carbon are particularly preferable. These palladium catalysts can be used alone or in combination. When the palladium or palladium hydroxide is supported on the carrier, the supported content may be 0.1 to 50% by weight, preferably 0.5 to 40% by weight, and particularly preferably 1 to 30% by weight. A water-containing product can also be used as the palladium catalyst. Furthermore, in order to increase the safety of handling or prevent the oxidation of the metal surface, the one stored in water or an inert liquid can also be used. Finally, it is possible to reuse the palladium catalyst recovered from the reaction end solution in the after-treatment described later.

The amount of the palladium catalyst used may be 0.05 mol or less, preferably 0.00001 to 0.03 mol, relative to 1 mol of optically active 3-dibenzylamino-2-fluoropropionic acid ester [1]. 0.0001 to 0.01 mol is particularly preferred.

The hydrogen gas may be used in an amount of 2 moles or more per mole of optically active 3-dibenzylamino-2-fluoropropionic acid ester [1]. Is particularly preferred.

The pressure condition of hydrogen gas may be 5 MPa or less, preferably 0.005 to 4 MPa, and particularly preferably 0.01 to 3 MPa. Therefore, it is preferable to use a pressure resistant reaction vessel made of a material such as stainless steel (SUS) or glass (glass lining).

In the first step, it is preferable to carry out dedibenzylation by adding an acid as an additive because the reaction proceeds very smoothly ([Invention 2]). However, by employing a combination of suitable reaction conditions, it is not always necessary to add an additive in the first step.

Examples of the additive include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid and nitric acid, and organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid and paratoluenesulfonic acid. Among these, hydrogen chloride, hydrogen bromide, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and paratoluenesulfonic acid are preferable, and hydrogen chloride, acetic acid, trifluoroacetic acid and paratoluenesulfonic acid are particularly preferable. These acids can be used alone or in combination.

When the additive is used, the amount used may be 0.1 mol or more per mol of optically active 3-dibenzylamino-2-fluoropropionic acid ester [1], preferably 0.2 to 100 mol. 0.3 to 50 mol is particularly preferred.

Examples of the reaction solvent include ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, n-butanol, 2,2,2-triol. Examples thereof include alcohols such as fluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, water, and the like. Of these, alcohols are preferred, and methanol, ethanol, n-propanol and isopropanol are particularly preferred. These reaction solvents can be used alone or in combination.

The reaction solvent may be used in an amount of 0.05 L (liter) or more, preferably 0.1 to 20 L, based on 1 mol of optically active 3-dibenzylamino-2-fluoropropionic acid ester [1]. .15 to 10 L is particularly preferred.

The reaction temperature may be + 150 ° C. or less, preferably −30 ° C. to + 100 ° C., particularly preferably −20 ° C. to + 50 ° C.

The reaction time may be 48 hours or less, but it varies depending on the reaction substrate and reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, and nuclear magnetic resonance. The end point is preferably the time point at which almost no decrease in the reaction substrate is observed.

In the first step, the target optically active 3-amino-2-fluoropropionic acid ester [2] can be obtained by performing a general post-treatment operation in organic synthesis on the reaction end solution. Preferably, an operation of filtering the palladium catalyst in the reaction completion liquid and concentrating the filtrate washing liquid to obtain a residue is effective. By this operation, the target product having high water solubility can also be recovered with high yield. The stereochemistry at the 2-position of the target product is maintained throughout this step, and no decrease in optical purity is observed. Moreover, it can also refine | purify by column chromatography etc. as needed.

In particular, the optically active 3-amino-2-fluoropropionic acid ester [2] produced in the first step is preferable because it can be obtained as a high-purity product by conducting salt purification by inducing a salt with an acid. ([Invention 3]). The actual operations are “induction to a salt with an acid” and “salt purification”, but they can be performed as general operations in organic synthesis. I Basics of experiments and information, published by Maruzen in 2003), 4 (Basics IV IV Organic / Polymer / Biochemistry, published by Maruzen in 2003), 5 (Basic technologies for chemical experiments, published by Maruzen in 2005) It can be performed in the same manner with reference to the like.] These operations can be carried out using a solvent (hereinafter referred to as a salt-inducing solvent and a salt-purifying solvent, respectively) used in “derivation to a salt with an acid” or “salt purification” as described below, as necessary.

The specific operation of “induction to a salt with an acid” is not particularly limited, but is preferably performed by adding an acid to the reaction completion liquid, the filtrate washing liquid or the concentrated residue. By adding an acid before the concentration, the target product having a low boiling point can be recovered in a high yield as a salt. In addition, when an acid is added to the concentrated residue, it is effective to use a salt-derived solvent. Furthermore, activated carbon treatment, concentration of a salt-derived solvent, and the like can be performed in an arbitrary process as necessary.

Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid and nitric acid, formic acid, acetic acid, propionic acid, benzoic acid, trifluoroacetic acid, mandelic acid (R-form, S-form or racemic form), oxalic acid, malee Examples include acids, fumaric acid, phthalic acid, malic acid (D-form, L-form or racemic form), tartaric acid (D-form, L-form or racemic form), methanesulfonic acid, paratoluenesulfonic acid and the like. Of these, hydrogen chloride, hydrogen bromide, sulfuric acid, acetic acid, trifluoroacetic acid, oxalic acid, fumaric acid, phthalic acid, malic acid, tartaric acid, methanesulfonic acid, and paratoluenesulfonic acid are preferred. Hydrogen chloride, acetic acid, trifluoroacetic acid Particularly preferred are oxalic acid, phthalic acid, tartaric acid and paratoluenesulfonic acid. It is also possible to combine the acid of the additive for making the reaction proceed very smoothly and the acid of “derivation to the salt with the acid”. You can handle it.

The amount of the acid used may be 0.35 mol or more, preferably 0.4 to 10 mol, preferably 0.45 to 5 per 1 mol of optically active 3-amino-2-fluoropropionic acid ester [2]. Mole is particularly preferred.

The specific operation of “salt purification” is not particularly limited, but is preferably performed by “isolation with crystals”, “washing of isolated crystals” or “recrystallization of isolated crystals”. “Salt refining” can be applied to non-crystallized salts (for example, oily substances, viscous liquids, cakes, amorphouss, etc.). A method of stirring and washing, a method of separating (or separating) and recovering by adding a poor solvent after dissolving in a rich solvent, and the like can be employed. However, a salt that crystallizes is preferable because it has a higher purification efficiency, and in particular, “isolation with crystals” and “washing of isolated crystals” are easy to obtain, but easy to obtain a high-purity product. The “salt purification” can be performed by arbitrarily combining arbitrary operations depending on the required degree of purification. Moreover, it can also be purified to a higher purity by repeating the same operation. Furthermore, activated carbon treatment, salt purification solvent concentration, and the like can be performed in an arbitrary process as necessary. In “salt purification”, the chemical purity, optical purity, or both can be increased.

Solvents used for “induction to salt with acid” or “salt purification” include aliphatic hydrocarbons such as n-hexane, cyclohexane, n-heptane, n-octane, benzene, toluene, ethylbenzene, xylene, mesitylene Aromatic hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, etc., ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, 1,4-dioxane, acetone, methyl ethyl ketone , Ketone systems such as methyl isobutyl ketone, ester systems such as ethyl acetate and n-butyl acetate, amide systems such as N, N-dimethylformamide, N, N-dimethylacetamide and 1,3-dimethyl-2-imidazolidinone , Acetonitrile, propionitrile, etc. Tolyl based, dimethyl sulfoxide, methanol, ethanol, n- propanol, isopropanol, alcohol etc. n- butanol, water and the like. Among them, n-hexane, cyclohexane, n-heptane, toluene, ethylbenzene, xylene, methylene chloride, tetrahydrofuran, tert-butyl methyl ether, 1,4-dioxane, acetone, methyl ethyl ketone, ethyl acetate, N, N-dimethylformamide, 1 , 3-dimethyl-2-imidazolidinone, acetonitrile, dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropanol and water are preferred, n-hexane, n-heptane, toluene, xylene, methylene chloride, tetrahydrofuran, 1,4 -Dioxane, acetone, ethyl acetate, N, N-dimethylformamide, acetonitrile, methanol, ethanol, isopropanol and water are particularly preferred. These salt induction solvents or salt purification solvents can be used alone or in combination. Further, the reaction solvent, the salt-inducing solvent, and the salt purification solvent can be combined, and among them, it is preferable to combine any two solvents, and it is particularly preferable to combine three solvents.

The amount of the solvent used for the “derivation to a salt with an acid” or “salt purification” is 0.05 L with respect to 1 mol of the optically active 3-amino-2-fluoropropionic acid ester [2] or a salt of the compound. What is necessary is just to use the above, 0.07 to 20L is preferable, and 0.09 to 10L is especially preferable.

“Isolation by crystal” or “recrystallization of isolated crystal” may cause the crystal to precipitate smoothly and efficiently by adding a seed crystal (by using a combination of suitable purification conditions, There is no need to add seed crystals).

When the seed crystal is used, the amount used may be 0.00001 mol or more with respect to 1 mol of the salt of the optically active 3-amino-2-fluoropropionic acid ester [2], and 0.0001 to 0.1 mol. Is preferable, and 0.0002 to 0.05 mol is particularly preferable.

The temperature condition of “induction to salt with acid” or “salt purification” may be performed at + 150 ° C. or less, preferably −30 to + 125 ° C., particularly preferably −20 to + 100 ° C. In the case of “isolation with crystals” or “recrystallization of isolated crystals”, it is preferable to age at + 15 ° C. by gradually cooling or cooling.

The time condition of “derivation to salt with acid” or “salt purification” may be within 48 hours, but it varies depending on the basic substance and the induction or purification conditions. Therefore, gas chromatography, thin layer chromatography, liquid chromatography It is preferable that the progress of induction or purification is tracked by analytical means such as chromatography or nuclear magnetic resonance, and that the end point is when no further progress is observed.

The operation for recovering the salt obtained by “induction to a salt with an acid” is not particularly limited, but it is preferably used for “salt purification” in a solution or in a concentrated residue.

The operation for recovering the salt obtained by “salt purification” is not particularly limited, but preferably a high-purity product can be obtained by filtering, separating or separating crystals, oily substances, viscous liquids, cakes, amorphouss, etc. . Moreover, washing | cleaning with a poor solvent, drying, etc. can also be performed in arbitrary processes as needed. The salt of the optically active 3-amino-2-fluoropropionic acid ester [2] obtained as a high-purity product can be subjected to the tert-butoxycarbonylation in the next step as it is or converted back to the free base. The method for returning to the free base is not particularly limited, but preferably includes an operation in which the salt is neutralized with an aqueous solution of an inorganic base and extracted with an organic solvent, and the recovered organic layer is concentrated to obtain a residue. Moreover, it can also be dried with a desiccant (for example, anhydrous sodium sulfate, anhydrous magnesium sulfate, etc.), a vacuum pump, etc. in arbitrary processes as needed. This inorganic base can be arbitrarily selected from inorganic bases added as an additive in the second step described later. The organic solvent can be arbitrarily selected from those that can be separated from an aqueous solution of an inorganic base from among salt-derived solvents and salt-purifying solvents. However, it is preferable to use the salt as it is in the next step because the operation is simple.

Next, the tert-butoxycarbonylation in the second step will be described in detail.

As described above, in the case where “induction to a salt with an acid” and “salt purification” are performed in the first step, the optically active 3-amino-2-fluoropropionic acid ester [2] is left as a salt in this step. It can also be subjected to tert-butoxycarbonylation.

Boc of the target optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester [3] represents a tert-butoxycarbonyl group.

The amount of di-t-butyl dicarbonate used may be 0.7 mol or more per 1 mol of optically active 3-amino-2-fluoropropionic acid ester [2] or a salt of the compound. To 5 mol is preferred, and 0.9 to 3 mol is particularly preferred.

In the second step, it is preferable to carry out tert-butoxycarbonylation by adding a base as an additive because the reaction proceeds very smoothly ([Invention 2]). However, it is not necessary to add an additive by adopting a combination of suitable reaction conditions.

As additives, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and other inorganic bases, triethylamine, diisopropylethylamine, tri-n- Butylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine (DMAP), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1, And organic bases such as 8-diazabicyclo [5.4.0] undec-7-ene (DBU). Among them, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5 4.0] undec-7-ene is preferred, with sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine and 4-dimethylaminopyridine being particularly preferred. These bases can be used alone or in combination.

When the additive is used, the amount used may be 0.01 mol or more, preferably 0.03 to 5 mol, based on 1 mol of optically active 3-amino-2-fluoropropionic acid ester [2]. 0.05 to 3 moles is particularly preferred. When the optically active 3-amino-2-fluoropropionic acid ester [2] is used in this step in the form of a salt, it must be returned to the free base in the reaction system. In addition, a reaction may be performed. This base can be arbitrarily selected from the bases of additives for allowing the reaction to proceed very smoothly, but it is preferable to carry out the reaction with both of them being the same base.

Examples of the reaction solvent include aliphatic hydrocarbons such as n-hexane, cyclohexane, n-heptane, and n-octane, aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene, and mesitylene, methylene chloride, chloroform, 1, Halogens such as 2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, 1,4-dioxane, esters such as ethyl acetate and n-butyl acetate, acetonitrile, propionitrile, etc. Nitrile type, water and the like. Of these, n-hexane, cyclohexane, n-heptane, toluene, ethylbenzene, xylene, methylene chloride, tetrahydrofuran, tert-butyl methyl ether, 1,4-dioxane, ethyl acetate, acetonitrile and water are preferred, and n-hexane, n- Particularly preferred are heptane, toluene, xylene, methylene chloride, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetonitrile and water. These reaction solvents can be used alone or in combination. When water is used, the reaction can be performed in a heterogeneous system.

The reaction solvent may be used in an amount of 0.05 L or more with respect to 1 mol of optically active 3-amino-2-fluoropropionic acid ester [2] or a salt of the compound, preferably 0.1 to 20 L, .15 to 10 L is particularly preferred.

The reaction temperature may be + 150 ° C. or less, preferably −30 ° C. to + 125 ° C., particularly preferably −20 ° C. to + 100 ° C.

The reaction time may be 48 hours or less, but it varies depending on the reaction substrate and reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, and nuclear magnetic resonance. The end point is preferably the time point at which almost no decrease in the reaction substrate is observed.

In the second step, the target optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester [3] is obtained by performing a general post-treatment operation in organic synthesis on the reaction end solution. Can do. Preferably, the operation of washing the reaction end solution with an aqueous solution of an inorganic base and concentrating the recovered organic layer to obtain a residue is effective. Even when the amount of di-t-butyl dicarbonate used for the optically active 3-amino-2-fluoropropionic acid ester [2] is controlled to exactly 1 equivalent, unreacted di-t-butyl dicarbonate is the target product. Remain. If necessary, it can be purified by activated carbon treatment, column chromatography or the like. Further, the stereochemistry at the 2-position of the target product is maintained throughout this step, and no decrease in optical purity is observed.

In this way, the first step and the second step can produce optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester [3], which is a novel substance, as a key intermediate in the production method of the present invention. ([Invention 5]).

Finally, the hydride reduction in the third step will be described in detail.

The amount of lithium borohydride or sodium borohydride used may be 0.35 mol or more per 1 mol of optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester [3]. 4 to 5 mol is preferred, and 0.45 to 3 mol is particularly preferred.

Examples of the reaction solvent include ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, and 1,4-dioxane, and alcohols such as methanol, ethanol, n-propanol, isopropanol, and n-butanol. . Of these, tetrahydrofuran, tert-butyl methyl ether, 1,4-dioxane, methanol, ethanol, n-propanol and isopropanol are preferred, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol and isopropanol are particularly preferred. 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, preferably 0.1 to 20 L, based on 1 mol of optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester [3]. 15 to 10 L is particularly preferred.

The reaction temperature may be + 150 ° C. or less, preferably −50 ° C. to + 125 ° C., particularly preferably −40 ° C. to + 100 ° C.

The reaction time may be 48 hours or less, but it varies depending on the reaction substrate and reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, and nuclear magnetic resonance. The end point is preferably the time point at which almost no decrease in the reaction substrate is observed.

In the third step, the target optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol [4] is crystallized by subjecting the reaction end solution to a general post-treatment operation in organic synthesis. Can be obtained as Preferably, an operation of adding an aqueous solution of an inorganic base to the reaction completion liquid and concentrating, adding water to the residue and extracting with an organic solvent, washing the recovered organic layer with water, and concentrating to obtain a residue is effective. Even if a reaction substrate in which unreacted di-t-butyl dicarbonate remains is decomposed under the reaction conditions of this step, di-t-butyl dicarbonate does not remain at all in the target product. If necessary, it can be purified by activated carbon treatment, column chromatography or the like. Further, the stereochemistry at the 2-position of the target product is maintained throughout this step, and no decrease in optical purity is observed.

The optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol produced in the third step is preferable because it can be obtained as a high purity product by recrystallization purification ([Invention 3]). As an actual operation, it can be performed as a general operation in organic synthesis [The Chemical Society of Japan, edited by Fifth Edition, Experimental Chemistry Lecture 1 (Basics I: Basics of Experiments and Information, published by Maruzen in 2003), 4 (Basics Part IV IV Organic / Polymer / Biochemistry, published by Maruzen in 2003), 5 (Basic technology for chemical experiments, published by Maruzen in 2005), etc.] By repeating recrystallization purification, it can be purified to a higher purity. Moreover, activated carbon treatment etc. can also be performed as needed. In recrystallization purification, the purity of chemical purity, optical purity, or both can be increased.

Recrystallization solvents include n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, cycloheptane, n-octane, cyclooctane and other aliphatic hydrocarbons, benzene, toluene, ethylbenzene, xylene, mesitylene, etc. Aromatic hydrocarbons, halogens such as methylene chloride, chloroform, 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, 1,4-dioxane, acetone, methyl ethyl ketone, Ketones such as methyl isobutyl ketone, esters such as ethyl acetate and n-butyl acetate, nitriles such as acetonitrile and propionitrile, methanol, ethanol, n-propanol, isopropanol, n-butanol, etc. Alcohol, water and the like. Of these, aliphatic hydrocarbons, aromatic hydrocarbons and mixed solvents thereof are preferable, and n-hexane, cyclohexane, n-heptane, n-octane, toluene, ethylbenzene, xylene and mixed solvents thereof are particularly preferable. This recrystallization purification is preferable because a high-purity product can be recovered with good yield by using an aliphatic hydrocarbon type, an aromatic hydrocarbon type or a mixed solvent thereof as a recrystallization solvent ([Invention 4]). . These recrystallization solvents can be used alone or in combination.

The recrystallization solvent may be used in an amount of 0.05 L or more with respect to 1 mol of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol [4], preferably 0.07 to 20 L, 0.09 to 10 L is particularly preferred.

In the recrystallization purification, there is a case where crystals are precipitated smoothly and efficiently by adding a seed crystal (a combination of suitable recrystallization conditions is not necessarily required to add a seed crystal).

When the seed crystal is used, the amount used may be 0.00001 mol or more with respect to 1 mol of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol [4]. 0.1 mole is preferred, with 0.0002 to 0.05 mole being particularly preferred.

The temperature condition for recrystallization purification may be + 150 ° C. or less, preferably −30 ° C. to + 125 ° C., particularly preferably −20 ° C. to + 100 ° C. Moreover, it is preferable to age at + 15 ° C. or lower by gradually cooling or cooling.

The recrystallization purification time condition may be within 48 hours, but since it varies depending on the recrystallization substrate and the purification conditions, it can be purified by analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, nuclear magnetic resonance, etc. It is preferable that the progress is tracked and the end point is the point at which no further progress is recognized.

The operation for recovering the high-purity product obtained by recrystallization purification is not particularly limited. Preferably, the precipitated crystal is filtered, washed with a poor solvent as necessary, and dried at 30 ° C. or less to obtain high purity. Goods can be obtained.

EXAMPLES The present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

[Example 1]
90.4 g of methyl (R) -3-dibenzylamino-2-fluoropropionate represented by the following formula (gas chromatographic purity: 88) produced in the same manner from L-serine with reference to the pamphlet of International Publication No. 2009/133789 0.4%, 265 mmol, 1.00 eq) in methanol solution (solvent usage 300 mL, 0.9 M) and 5% palladium on carbon (water content 50%) 6.38 g (1.50 mmol, 0.00566 eq) Acetic acid 36.0 g (600 mmol, 2.26 eq) was added, the hydrogen gas pressure was set to 0.9 MPa, and the mixture was stirred at room temperature overnight.

The conversion rate was 100% from ¹⁹ F-NMR of the reaction completed liquid. The reaction-terminated liquid was filtered through Celite, washed with a small amount of methanol, and 13.0 g (357 mmol, 1.35 eq) of hydrogen chloride gas (HCl) was blown into the filtrate with ice cooling, followed by concentration under reduced pressure. Toluene (200 mL, 1.3 M) was added to the residue (crude crystals), and the mixture was stirred and washed under ice cooling (heterogeneous system). The crystals were filtered, washed with toluene (40 mL), and vacuum-dried. 28.8 g of methyl (R) -3-amino-2-fluoropropionate hydrochloride (purified crystals) was obtained.

The yield was 69%. ¹ H-NMR and ¹⁹ F-NMR are shown below.
¹ H-NMR [reference material; (CH ₃ ) ₄ Si, heavy solvent; CD ₃ OD]; δ ppm / 3.44 (m, 1H), 3.54 (m, 1H), 3.85 (s, 3H), 5.34 (m, 1H), the amino group and the proton of hydrochloric acid cannot be assigned.
¹⁹ F-NMR (reference material; C ₆ F ₆ , heavy solvent; CD ₃ OD); δ ppm / −34.31 (m, 1F).

15.0 g (95.2 mmol, 1.00 eq) of (R) -3-amino-2-fluoropropionic acid methyl hydrochloride (purified crystals) obtained above and 20.8 g (95 of di-t-butyl dicarbonate) .3 mmol, 1.00 eq) in toluene (solvent usage 95 mL, 1.0 M) was added 11.6 g (115 mmol, 1.21 eq) of triethylamine under ice-cooling and stirred at room temperature overnight. The reaction-terminated liquid was washed with an aqueous potassium carbonate solution [prepared from 13.2 g (95.5 mmol, 1.00 eq) of potassium carbonate and 60 mL of water], and the recovered organic layer was concentrated under reduced pressure and vacuum-dried, and expressed by the following formula. 21.4 g of methyl (R) -3-tert-butoxycarbonylamino-2-fluoropropionate (oil) was obtained (theoretical yield 21.1 g).

The purity by gas chromatography was 94.7% (3.7% of di-t-butyl dicarbonate remained, and the purity excluding di-t-butyl dicarbonate was 98.4%). ¹ H-NMR and ¹⁹ F-NMR are shown below.
¹ H-NMR [reference material; (CH ₃ ) ₄ Si, heavy solvent; CDCl ₃ ]; δ ppm / 1.44 (s, 9H), 3.65 (m, 2H), 3.81 (s, 3H ), 4.90 (br, 1H), 4.99 (m, 1H).
¹⁹ F-NMR (reference material; C ₆ F ₆ , heavy solvent; CDCl ₃ ); δ ppm / −34.89 (m, 1F).

A solution of 20.9 g (93.0 mmol, 1.00 eq) of methyl (R) -3-tert-butoxycarbonylamino-2-fluoropropionate (oil substance) obtained above (solvent use 70 mL, 1.3M) was added 2.68 g (70.8 mmol, 0.76 eq) of sodium borohydride under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour and further at room temperature for 4 hours. A potassium carbonate aqueous solution [prepared from 13.0 g (94.1 mmol, 1.01 eq) of potassium carbonate and 100 mL of water] was added to the reaction completion solution, and the mixture was concentrated under reduced pressure. 10 mL of water is added to the residue, followed by extraction with 100 mL of ethyl acetate, and the recovered organic layer is washed with 30 mL of water, concentrated under reduced pressure, and dried under vacuum to give (R) -3-tert-butoxycarbonylamino represented by the following formula. 17.7 g of -2-fluoro-1-propanol (white crystals) was obtained.

The total yield of the two steps from (R) -3-amino-2-fluoropropionic acid methyl hydrochloride (purified crystals) was 98%. The gas chromatographic purity was 97.3% (di-t-butyl dicarbonate was not detected). ¹ H-NMR and ¹⁹ F-NMR are shown below.
¹ H-NMR [reference material; (CH ₃ ) ₄ Si, heavy solvent; CDCl ₃ ]; δ ppm / 1.46 (s, 9H), 3.11 (br, 1H), 3.48 (m, 2H ), 3.70 (m, 2H), 4.59 (m, 1H), 4.90 (br, 1H).
¹⁹ F-NMR (reference material; C ₆ F ₆ , heavy solvent; CDCl ₃ ); δ ppm / −34.22 (m, 1F).

26 mL of toluene (3.5 M, 1.5 mL / g) was added to 17.5 g (90.6 mmol) of (R) -3-tert-butoxycarbonylamino-2-fluoro-1-propanol (white crystals) obtained above. The mixture was dissolved at 30 ° C., further added with 9 mL of n-heptane (10 M, 0.5 mL / g), cooled to 10 ° C., added with seed crystals, and aged at 0 ° C. The precipitated crystals are filtered, washed with 10 mL of pre-cooled n-heptane, and vacuum-dried at room temperature (25 ° C.) to give (R) -3-tert-butoxycarbonylamino-2-fluoro represented by the above formula. 13.9 g of a high purity product of -1-propanol (white crystals) was obtained. The recovery rate was 79%. The melting point was 39 ° C. The gas chromatography purity was 99.5%. The optical purity by chiral gas chromatography (after induction to Mosher's acid ester) was 100% ee. Furthermore, by repeating the same recrystallization purification using a mixed solvent of toluene and n-heptane (second recrystallization), the gas chromatography purity was improved to 99.9% (recovery rate 93%, optical purity 100). % Ee).

[Example 2]
Example 1 Using methyl (S) -3-dibenzylamino-2-fluoropropionate represented by the following formula, which was prepared in the same manner from D-serine with reference to the pamphlet of International Publication No. 2009/133789, as a starting material, Example 1 The reaction (debenzylation, tert-butoxycarbonylation, hydride reduction) was carried out in the same manner as described above.

As a result, (S) -3-tert-butoxycarbonylamino-2-fluoro-1-propanol represented by the following formula could be produced.

The color tone, physical properties, yield, total yield, gas chromatography purity, ¹ H-NMR and ¹⁹ F-NMR of the final product obtained were the same as in Example 1 (other than the absolute configuration of the asymmetric carbon). . The color tone, physical properties, recovery amount, recovery rate, melting point, gas chromatography purity and optical purity in recrystallization purification were also the same as in Example 1. Further, the gas chromatography purity, recovery rate and optical purity in the second recrystallization were also the same as in Example 1.

[Reference Example 1]
70.0 g of (R) -3-dibenzylamino-2-fluoro-1-propanol represented by the following formula (gas chromatographic purity: 94.5%) produced in the same manner from L-serine with reference to Patent Document 1 To a 242 mmol, 1.00 eq) methanol solution (solvent usage 256 mL, 0.9 M), 7.27 g (1.71 mmol, 0.00707 eq) of 5% palladium on carbon (water content 50%) and acetic acid 46. 1 g (768 mmol, 3.17 eq) was added.

The resulting reaction mixture was stirred under hydrogen gas at a pressure of 0.9 MPa, and the progress of the reaction was followed by ¹⁹ F-NMR. The reaction check (1) was performed “after stirring overnight at room temperature”, and the reaction check (2) was performed “after further stirring overnight at 50 ° C.”. After the reaction check (2), the reaction mixture was filtered through Celite, and 70% of the filtrate (to 169 mmol, 1.00 eq) was added to 5.09 g [1.20 mmol, 0% of 5% palladium carbon (water content 50%). .00710 eq (total usage 0.01417 eq)] was added again. The resulting mixture was stirred under hydrogen gas at a pressure of 0.9 MPa, and the progress of the reaction was followed by ¹⁹ F-NMR. A reaction check (3) was performed “after 3 hours of stirring at room temperature”, and a reaction check (4) was performed “after further stirring overnight at room temperature”.

Table 1 summarizes the composition ratios (dibenzyl: monobenzyl: target) of the reaction mixture in each reaction check.

The ¹⁹ F-NMR (reference material: C ₆ F ₆ , heavy solvent: CD ₃ OD) of the reaction mixture in the reaction check is shown below.
(R) -3-dibenzylamino-2-fluoro-1-propanol (dibenzyl form) represented by the above formula; δ ppm / −25.51 (m, 1F).
(R) -3-benzylamino-2-fluoro-1-propanol (monobenzyl form) represented by the following formula; δ ppm / −29.72 (m, 1F).

(R) -3-amino-2-fluoro-1-propanol represented by the following formula (target product); δ ppm / −32.38 (m, 1F).

As described above, in the method for producing optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol of the present invention, the amount of palladium catalyst used is significantly reduced by performing debenzylation in the first step. Since the reaction can be completed in one time, the production cost is low and the operation is simple. In addition, a high-purity product can be obtained by crystallization of the final target product and recrystallization purification. Therefore, according to the present invention, optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol can be produced industrially more advantageously than the prior art.

Although the embodiments of the present invention have been described above, it is needless to say that the following embodiments can be appropriately changed and improved based on the ordinary knowledge of those skilled in the art without departing from the spirit of the present invention. Absent.

Claims (5)

1. The optically active 3-dibenzylamino-2-fluoropropionic acid ester represented by the general formula [1] is dedibenzylated with hydrogen gas (H ₂ ) in the presence of a palladium catalyst, and represented by the general formula [2]. A first step of converting to an optically active 3-amino-2-fluoropropionic acid ester, and an ester represented by the general formula [2] with tert-butoxycarbonyl di-t-butyl dicarbonate [(Boc) ₂ O] A second step of converting to an optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester represented by the general formula [3] by converting the ester compound represented by the general formula [3] to borohydride lithium light represented by (LiBH ₄₎ or sodium borohydride and a third step of hydride reduction with (NaBH _4), the general formula [4] Production method of the active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol.
   

   

   

   

   

   [Wherein, R represents an alkyl group having 1 to 6 carbon atoms, Bn represents a benzyl group, Boc represents a tert-butoxycarbonyl group, and * represents an asymmetric carbon. ]
2. The process according to claim 1, wherein the dedibenzylation in the first step is performed by adding an acid as an additive, and further the tert-butoxycarbonylation in the second step is performed by adding a base as an additive. .
3. The optically active 3-tert-2-butoxycarbonylamino-2 obtained in the third step is subjected to salt purification by derivatizing the optically active 3-amino-2-fluoropropionic acid ester obtained in the first step into a salt with an acid. 3. The production method according to claim 1, wherein recrystallization purification of fluoro-1-propanol is performed.
4. The recrystallization solvent of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol obtained in the third step is an aliphatic hydrocarbon type, an aromatic hydrocarbon type or a mixed solvent thereof. The manufacturing method according to claim 3.
5. An optically active 3-tert-butoxycarbonylamino-2-fluoropropionate represented by the general formula [3].
   

   

   [Wherein, R represents an alkyl group having 1 to 6 carbon atoms, Boc represents a tert-butoxycarbonyl group, and * represents an asymmetric carbon. ]