阅读说明：本技术 光学活性的2－氨基－膦酰基烷酸、光学活性的2－氨基－膦酰基烷酸盐及它们的水合物 (Optically active 2- amino-phosphono alkanoic acid, optically active 2- amino-phosphonoalkyl hydrochlorate and their hydrate ) 是由 渡边文太 吉冈龙藏 石田英晃 于 2018-04-13 设计创作，主要内容包括：本发明提供具有与NAHLSGEN同样的药理活性且保存稳定性优异的新型的化合物、及其制造方法。本发明的光学活性的2－氨基－膦酰基烷酸盐的制造方法,其特征在于,使碱性光学活性化合物(其中,光学活性赖氨酸除外)与作为原料的下述式(1)所示的DL－2－氨基－膦酰基烷酸或其水合物反应,得到下述式(1－1)所示的D－2－氨基－膦酰基烷酸与上述碱性光学活性化合物的盐(包括水合物)、和下述式(1－2)所示的L－2－氨基－膦酰基烷酸与上述碱性光学活性化合物的盐(包括水合物)的非对映体盐混合物,将得到的非对映体盐混合物供于分步结晶而单离一种非对映体盐。<Image he="756" wi="700" file="DDA0002234616820000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention provides the novel compound and its manufacturing method with pharmacological activity same as NAHLSGEN and excellent storage stability.The manufacturing method of optically active 2- amino-phosphonoalkyl hydrochlorate of the invention, it is characterized in that, make alkaline optically active compound (wherein, except optical activity lysine) with DL-2- amino-phosphono alkanoic acid or its hydrate reaction shown in following formula (1) as raw material, obtain the salt (including hydrate) of D-2- amino-phosphono alkanoic acid shown in following formula (1-1) and above-mentioned alkaline optically active compound, with the diastereomer salt mixture of L-2- amino-phosphono alkanoic acid shown in following formula (1-2) and the salt (including hydrate) of above-mentioned alkaline optically active compound, by obtained diastereomer salt mixture for fractional crystallization a kind of isolated diastereoisomeric salt.)

1. a kind of manufacturing method of optically active 2- amino-phosphonoalkyl hydrochlorate, which is characterized in that

Make alkaline optically active compound and DL-2- amino-phosphono alkanoic acid shown in following formula (1) as raw material or Its hydrate reaction obtains D-2- amino-phosphono alkanoic acid shown in following formula (1-1) and the alkaline optical activity L-2- amino-phosphono alkanoic acid shown in the salt and following formula (1-2) of conjunction object and the alkaline optically active compound The diastereomer salt mixture of salt, by obtained diastereomer salt mixture for fractional crystallization, and a kind of isolated diastereomer Salt,

Wherein, the alkaline optically active compound does not include optical activity lysine, the D-2- amino-phosphonoalkyl It is sour living with the salt and L-2- amino-phosphono alkanoic acid of the alkaline optically active compound and the alkaline optics The salt of property compound includes hydrate,

In formula (1), m indicates that 1~7 integer, * indicate asymmetric atom,

In formula (1-1), m, * are same as described above,

In formula (1-2), m, * are same as described above.

2. the manufacturing method of optically active 2- amino-phosphonoalkyl hydrochlorate according to claim 1, wherein

Alkaline optically active compound is selected from cinchonine, cinchonidine, quinine, chinidine, optically active arginine, optics Active phenylalanyl amine, optically active ornithine, optically active tyrosine hydrazides, optically active 1- phenylpropylamine, Optically active 2- phenylpropylamine, optically active valerian ammonia alcohol, optically active p-hydroxybenzene glycine hydrazides, optics are living P-hydroxybenzene glycine methyl ester, the optically active p-hydroxybenzene glycine ethyl ester, optically active aminoglucose, optics of property Compound in active leucinol, optically active 1- phenylethylamine and optically active 2- amino-n-butyl alcohol.

3. the manufacturing method of optically active 2- amino-phosphonoalkyl hydrochlorate according to claim 1 or 2, wherein

As raw material, the DL-2- amino-phosphono alkanoic acid for being 1,3 or 5 of the m shown in formula (1) and in formula or its hydration are used Object.

4. the manufacturer of optically active 2- amino-phosphonoalkyl hydrochlorate described in any one of claim 1 to 3 Method, wherein

DL-2- amino-phosphono alkanoic acid hydrate shown in formula (1) is used to obtain as raw material as diastereoisomeric salt , the salt of D-2- amino-phosphono alkanoic acid shown in formula (1-1) and alkaline optically active compound or its hydrate or The salt or its hydrate of L-2- amino-phosphono alkanoic acid shown in person's formula (1-2) and alkaline optically active compound.

5.D-2- amino-phosphonoalkyl hydrochlorate or its hydrate, as shown in following formula (1-1 '-B),

In formula (1-1 '-B), m ' indicates that 1,3 or 5, t indicate that 0~5 number, Bs indicate that alkaline optically active compound, * indicate Asymmetric atom, wherein the alkalinity optically active compound does not include optical activity lysine.

6.L-2- amino-phosphonoalkyl hydrochlorate or its hydrate, as shown in following formula (1-2 '-B),

In formula (1-2 '-B), m ' indicates that 1,3 or 5, t ' indicate that 0~5 number, Bs indicate that alkaline optically active compound, * indicate Asymmetric atom, wherein the alkalinity optically active compound does not include optical activity lysine.

7. the manufacturing method of optically active 2- amino-phosphono alkanoic acid or its hydrate, which is characterized in that

It is obtained by the manufacturing method of optically active 2- amino-phosphonoalkyl hydrochlorate according to any one of claims 1 to 4 It to after optically active 2- amino-phosphonoalkyl hydrochlorate, is decomposed, obtains having identical with the compound processed Steric configuration, corresponding optically active 2- amino-phosphono alkanoic acid or its hydrate,

Wherein, the 2- amino-phosphonoalkyl hydrochlorate includes hydrate.

8. D-2- amino-phosphonoalkyl acid hydrate shown in following formula (1-1 '),

In formula (1-1 '), m ' indicates that 1,3 or 5, n represent more than 0 and be 5 numbers below, and * indicates asymmetric atom.

9. L-2- amino-phosphonoalkyl acid hydrate shown in following formula (1-2 '),

In formula (1-2 '), m ' indicates that 1,3 or 5, n represent more than 0 and be 5 numbers below, and * indicates asymmetric atom.

Technical field

The present invention relates to optically active 2- amino-phosphono alkanoic acids, optically active 2- amino-phosphono alkanoic acid Salt and their hydrate and their manufacturing method.It is special in the Japan of Japanese publication that this application claims on April 17th, 2017 It is willing to No. 2017-081237 priority, its content is incorporated herein.

Background technique

NAHLSGEN (registered trademark) or GGsTop [common name: DL-2- amino -4- [(RSp)-(3- carboxyl first Phenoxyl) (methoxyl group) phosphoryl] butyric acid] it is known (patent document 1 etc.) as excellent GGT inhibitor.

But NAHLSGEN at room temperature not crystallization but be in oily, the nothing obtained reluctantly for freeze-drying is fixed The powder solid of shape also has hygroscopy, is easy to decompose at room temperature.Therefore, it is necessary to Leng KURA or freezen protectives, it is very difficult to locate Reason.

Summary of the invention

Subject to be solved by the invention

Therefore, the object of the present invention is to provide have pharmacological activity same as NAHLSGEN and storage stability it is excellent Different novel compound and its manufacturing method.

Another object of the present invention is to provide will efficiently constitute 2 kinds of optics of DL-2- amino-phosphono alkanoic acid The isolated method of isomers.

Means for solving the problems

The present inventors has made intensive studies in order to solve the above problems.

Known 2- amino -5- phosphonopentanoic acid, the 2- amino -7- phosphono with NAHLSGEN with common skeleton Base enanthic acid is the mixture (racemic modification) of 2 kinds of optical isomers, carries out optical resolution using optically active lysine.

For total carbon number 4 including 2- amino -5- phosphonopentanoic acid, 2- amino -7- phosphono enanthic acid~ 10 DL-2- amino-phosphono alkanoic acid, the present inventors, which has found, can form with these with good crystalline Alkaline optically active compound other than salt, lysine.

Additionally, it was found that: D- or L-2- amino-phosphono alkanoic acid and above-mentioned alkalinity by isolated total carbon number 4~10 The salt of optically active compound, then by it for resolution process, so as to easily and efficiently obtain the D- of total carbon number 4~10 Or L-2- amino-phosphono alkanoic acid.

It was found that: in particular, D- or L-2- amino-phosphono alkanoic acid of total carbon number 4,6 or 8 and above-mentioned alkaline optics are living The salt of property compound or the crystallinity of its hydrate (that is, aqueous salt) are especially excellent, its is isolated, then for resolution process, by This can with high-purity and be efficiently obtained total carbon number 4,6 or 8 D- or L-2- amino-phosphono alkanoic acid or its hydration Object.

Moreover, it has been found that: pass through D- or L-2- amino-phosphonoalkyl of total carbon number 4,6 or 8 obtained by the above method Acid, they with the salt of alkaline optically active compound or their hydrate with pharmacological activity same as NAHLSGEN (such as collagen generates facilitation effect, glutathione generates facilitation effect, wound repair facilitation effect) and excellent storage stability. The present invention is completed based on these opinions.

That is, the present invention provides a kind of manufacturing method of optically active 2- amino-phosphonoalkyl hydrochlorate, feature exists In, make alkaline optically active compound (wherein, except optical activity lysine) with shown in following formula (1) as raw material DL-2- amino-phosphono alkanoic acid or its hydrate reaction obtain D-2- amino-phosphono shown in following formula (1-1) L-2- ammonia shown in the salt (including hydrate) and following formula (1-2) of base alkanoic acid and above-mentioned alkaline optically active compound The diastereomer salt mixture of the salt (including hydrate) of base-phosphono alkanoic acid and above-mentioned alkaline optically active compound, will A kind of diastereomer salt mixture arrived isolated diastereoisomeric salt for fractional crystallization.

[changing 1]

(in formula, m indicates that 1~7 integer, * indicate asymmetric atom)

[changing 2]

(in formula, m, * are same as described above)

[changing 3]

(in formula, m, * are same as described above)

In addition, the present invention provides the manufacturing method of above-mentioned optically active 2- amino-phosphonoalkyl hydrochlorate, wherein Alkaline optically active compound is selected from cinchonine, cinchonidine, quinine, chinidine, optically active arginine, optical activity Phenylalanyl amine, optically active ornithine, optically active tyrosine hydrazides, optically active 1- phenylpropylamine, optics It is active 2- phenylpropylamine, optically active valerian ammonia alcohol, optically active p-hydroxybenzene glycine hydrazides, optically active P-hydroxybenzene glycine methyl ester, optically active p-hydroxybenzene glycine ethyl ester, optically active aminoglucose, optical activity Leucinol, the compound in optically active 1- phenylethylamine and optically active 2- amino-n-butyl alcohol.

In addition, the present invention provides the manufacturing method of above-mentioned optically active 2- amino-phosphonoalkyl hydrochlorate, wherein As raw material, the DL-2- amino-phosphono alkanoic acid or its hydrate for the use of the m shown in formula (1) and in formula being 1,3 or 5.

In addition, the present invention provides the manufacturing method of above-mentioned optically active 2- amino-phosphonoalkyl hydrochlorate, wherein Use DL-2- amino-phosphono alkanoic acid hydrate shown in formula (1) as raw material, obtain it is as diastereoisomeric salt, The salt or its hydrate or formula of D-2- amino-phosphono alkanoic acid shown in formula (1-1) and alkaline optically active compound The salt or its hydrate of the amino of L-2- shown in (1-2)-phosphono alkanoic acid and alkaline optically active compound.

In addition, the present invention provides D-2- amino-phosphonoalkyl hydrochlorate shown in following formula (1-1 '-B) or its hydration Object.

[changing 4]

(in formula, m ' indicates 1,3 or 5, and t indicates 0~5 number.Bs indicates alkaline optically active compound, and (wherein, optics is living Except property lysine).* asymmetric atom is indicated)

In addition, the present invention provides L-2- amino-phosphonoalkyl hydrochlorate shown in following formula (1-2 '-B) or its hydration Object.

[changing 5]

(in formula, m ' indicates that 1,3 or 5, t ' indicate 0~5 number.Bs indicates alkaline optically active compound (wherein, optics Except REACTIVE LYSINE).* asymmetric atom is indicated)

In addition, the present invention provides optically active 2- amino-phosphono alkanoic acid or the manufacturing method of its hydrate, it is special Sign is, obtains optically active 2- in the manufacturing method by above-mentioned optically active 2- amino-phosphonoalkyl hydrochlorate It after amino-phosphonoalkyl hydrochlorate (including hydrate), is decomposed, obtains that there is sky identical with above-mentioned compound processed Between configuration, corresponding optically active 2- amino-phosphono alkanoic acid or its hydrate.

In addition, the present invention provides D-2- amino-phosphonoalkyl acid hydrate shown in following formula (1-1 ').

[changing 6]

(in formula, m ' indicates 1,3 or 5, and n represents more than 0 and 5 numbers below.* asymmetric atom is indicated)

In addition, the present invention provides L-2- amino-phosphonoalkyl acid hydrate shown in following formula (1-2 ').

[changing 7]

(in formula, m ' indicates 1,3 or 5, and n represents more than 0 and 5 numbers below.* asymmetric atom is indicated)

Invention effect

DL-2- amino-phosphono alkanoic acid shown in above-mentioned formula (1) or its hydrate have common with NAHLSGEN Skeleton, but can be easy compared with NAHLSGEN and be manufactured inexpensively.In addition, although the compound is 2 kinds of optical isomers Mixture (racemic modification), but the manufacturing method of optically active 2- amino-phosphonoalkyl hydrochlorate according to the present invention and The manufacturing method of optically active 2- amino-phosphono alkanoic acid or its hydrate, can a kind of efficiently isolated diastereomer Salt is [that is, the salt (including hydrate) or L- of D-2- amino-phosphono alkanoic acid and above-mentioned alkaline optically active compound The salt (including hydrate) of 2- amino-phosphono alkanoic acid and above-mentioned alkaline optically active compound], if by it is isolated go out it is non-right Body salt is reflected for resolution process, then obtains as decomposition product, optically active D-2- amino-phosphine to easy and high-purity Acyl group alkanoic acid or its hydrate or L-2- amino-phosphono alkanoic acid or its hydrate.

In addition, excellent by the crystallinity of diastereoisomeric salt obtained by the above method or its decomposition product.And in room temperature It is non-hygroscopic, it is nondeliquescent.Therefore, excellent storage stability is easily handled.In addition, having pharmacology same as NAHLSGEN Activity is (for example, collagen generates facilitation effect, glutathione generates mucous membranes such as facilitation effect, oral mucosa and eye mucous membranes etc. Wound repair facilitation effect) and do not have cytotoxicity, safety is excellent, it may be thus possible, for example, to be suitably used for anaphylaxis skin The skin diseases such as skin disease, ichthyosis vulgaris, senile xerosis；The mucous membrane disease of the oral mucosas such as periodontosis, conjunctivitis and eye The treatment or prevention purpose of disease.

Detailed description of the invention

Fig. 1 is the heat analysis knot for showing DL-2- amino -4- phosphonobutyric acid monohydrate obtained in preparation example 1 The figure of fruit.

Fig. 2 is the heat analysis knot for showing DL-2- amino -6- phosphono caproic acid monohydrate obtained in preparation example 3 The figure of fruit.

Fig. 3 is the heat analysis knot for showing DL-2- amino -8- phosphono octanoic acid monohydrate obtained in preparation example 5 The figure of fruit.

Fig. 4 is the heat analysis knot for showing DL-2- amino -10- phosphono capric acid monohydrate obtained in preparation example 7 The figure of fruit.

Fig. 5 is the heat analysis result for showing L-2- amino -4- phosphonobutyric acid monohydrate obtained in embodiment 2 Figure.

Fig. 6 is to show D-2- amino -6- phosphono caproic acid L-HPGM salt monohydrate obtained in embodiment 6 Heat analysis result figure.

Fig. 7 is the heat analysis result for showing D-2- amino -6- phosphono caproic acid monohydrate obtained in embodiment 6 Figure.

Fig. 8 is to show L-2- amino -8- phosphono octanoic acid D-HPGH salt monohydrate obtained in embodiment 8 Heat analysis result figure.

Fig. 9 is the heat analysis result for showing D-2- amino -8- phosphono octanoic acid monohydrate obtained in embodiment 8 Figure.

Specific embodiment

[manufacturing method of optically active 2- amino-phosphonoalkyl hydrochlorate]

The manufacturing method of optically active 2- amino-phosphonoalkyl hydrochlorate of the invention is characterized in that, makes alkaline light Reactive compound is learned (wherein, except optical activity lysine.Hereafter it is sometimes referred to as " Bs ") and as raw material, following formula (1) Shown in DL-2- amino-phosphono alkanoic acid (being hereafter sometimes referred to as " DL-AP ") or its hydrate reaction, obtain following formula The amino of D-2- shown in (1-1)-phosphono alkanoic acid (being hereafter sometimes referred to as " D-AP ") and above-mentioned alkaline optical activity chemical combination L-2- amino-phosphono alkanoic acid shown in the salt (including hydrate) and following formula (1-2) of object (is hereafter sometimes referred to as " L-AP ") (there are diastereomeric with the diastereomer salt mixture of the salt (including hydrate) of above-mentioned alkaline optically active compound The mixture of a pair of of salt of body relationship), by obtained diastereomer salt mixture for fractional crystallization, and isolated one kind is diastereomeric Body salt (there are the sides in a pair of of salt of diastereomer relationship).It should be noted that in following formula, m indicate 1~7 it is whole Number, * indicate asymmetric atom

[changing 8]

[changing 9]

[changing 10]

DL-AP is the mixing of two kinds of optical isomers due to having 1 asymmetric atom (*) in 1 molecule Object.In above-mentioned formula, (D), (L) are the symbols that the steric configuration for the ligand for being bonded to asymmetric atom is indicated with D-L representation Number, in the Fischer projection that carboxyl is placed in top, (D) indicates that amino is located at right side, and (L) indicates that amino is located at left side.It needs It is noted that the steric configuration of the optical isomer other than amino acid is indicated with R-S representation in this specification.

As above-mentioned raw materials, in particular, from the angle for obtaining the superior diastereoisomeric salt of crystallinity, it is preferable to use The compound that m shown in formula (1) and in formula is 1,3 or 5 is (that is, DL-2- amino-phosphonoalkyl that total carbon number is 4,6 or 8 Acid) or its hydrate.

In addition, as above-mentioned raw materials, from the angle for obtaining the superior diastereoisomeric salt of crystallinity, it is preferable to use The hydrate of DL-AP.

Therefore, as above-mentioned raw materials, it is preferable to use the hydrate for the compound that the m shown in formula (1) and in formula is 1,3 or 5 (that is, DL-2- amino-phosphonoalkyl acid hydrate that total carbon number is 4,6 or 8).

As above-mentioned alkaline optically active compound (Bs), it can be mentioned, for example: cinchonine, cinchonidine, quinine, Kui Ni Fixed, optically active arginine, optically active phenylalanyl amine, optically active ornithine, optically active tyrosine acyl It is hydrazine, optically active 1- phenylpropylamine, optically active 2- phenylpropylamine, optically active valerian ammonia alcohol, optically active right Hydroxyphenyl hydrazides, optically active p-hydroxybenzene glycine methyl ester, optically active p-hydroxybenzene glycine Ethyl ester, optically active aminoglucose, optically active leucinol, optically active 1- phenylethylamine, optically active 2- ammonia Base-n-butyl alcohol etc..It should be noted that cinchonine and cinchonidine optical isomer each other, quinine and chinidine are also each other Optical isomer.When above-mentioned optically active compound is amino acid, which includes D body (D-Bs) and L body (L- Bs), for example, optically active arginine includes D-Arg and L-arginine.It is ammonia in above-mentioned optically active compound Base acid other than compound when, the compound include R body (R-Bs) and S body (S-Bs), for example, optically active 1- phenyl Propylamine includes (R) -1- phenylpropylamine and (S) -1- phenylpropylamine.

If reacting DL-AP or its hydrate with alkaline optically active compound, D-AP and alkaline light can be formed The salt or its hydrate and L-AP and the alkaline salt of optically active compound or the mixture of its hydrate of reactive compound (diastereomer salt mixture).

For example, when using amino acid as alkalinity optically active compound (Bs), if making L body (L-Bs) and DL- AP or its hydrate reaction then obtain the salt comprising D-AP and L body (L-Bs) or its hydrate and L-AP and L body (L- Bs the diastereomer salt mixture of a pair of of diastereoisomeric salt of salt or its hydrate)；If making D body (D-Bs) and DL-AP Or its hydrate reaction, then obtain the salt comprising D-AP and D body (D-Bs) or its hydrate and L-AP and D body (D-Bs) Salt or its hydrate a pair of of diastereoisomeric salt diastereomer salt mixture.Alkaline optics other than using amino acid is living When property compound, also so.

It is just suitable for selecting using alkaline optical activity according to the length of the alkane chain of DL-AP (that is, m value in formula (1)) For the mode for closing object, from the diastereomer salt mixture comprising the superior diastereoisomeric salt of crystallinity can be formed, pass through A kind of diastereoisomeric salt for keeping above-mentioned crystallinity excellent is precipitated, so as to efficiently isolated from diastereomer salt mixture The angle of the diastereoisomeric salt of higher purity is set out, and which is preferred.

The preferred combination of DL-AP or its hydrate and alkaline optically active compound is as follows.

In formula (1),

When m=1, DL-2- amino -4- phosphonobutyric acid or when its hydrate, as alkaline optical activity chemical combination Object, preferably cinchonine, cinchonidine, quinine, chinidine, optically active arginine (D- or L-arginine), optical activity Phenylalanyl amine (D- or L- phenylalanyl amine) or optically active ornithine (D- or L-Orn).

When m=3, DL-2- amino -6- phosphono caproic acid or when its hydrate, as alkaline optical activity chemical combination Object, preferably optically active tyrosine hydrazides (D- or l-tyrosine hydrazides), optically active 1- phenylpropylamine (R- or S-1- phenylpropylamine), optically active valerian ammonia alcohol (D- or L- valerian ammonia alcohol), optically active p-hydroxybenzene glycine first Ester (D- or L- p-hydroxybenzene glycine methyl ester), optically active phenylalanyl amine (D- or L- phenylalanyl amine), light Learn active p-hydroxybenzene glycine hydrazides (D- or L- p-hydroxybenzene glycine hydrazides) or optically active pair of hydroxyl Phenylglycine ethyl ester (D- or L- p-hydroxybenzene glycine ethyl ester).

When m=5, DL-2- amino -8- phosphono octanoic acid or when its hydrate, as alkaline optical activity chemical combination Object, preferably optically active aminoglucose (D- or L- aminoglucose), optically active valerian ammonia alcohol (D- or L- valerian ammonia alcohol), optics Active leucinol (D- or L- leucinol), optically active 1- phenylethylamine (R- or S-1- phenylethylamine), optics Active p-hydroxybenzene glycine hydrazides (D- or L- p-hydroxybenzene glycine hydrazides) or optically active 2- ammonia Base-n-butyl alcohol (R- or S-2- amino-n-butyl alcohol).

As the usage amount of above-mentioned alkaline optically active compound, for example relative to DL-AP or its hydrate (1 mole) It is 0.5~2.0 mole or so, preferably 0.5~1.5 mole, particularly preferably 0.6~1.1 mole.

DL-AP or its hydrate preferably carry out in the presence of solvent with alkaline reacting for optically active compound, as molten Agent, it can be mentioned, for example: the ketone such as acetone, methyl ethyl ketone；The alcohol such as methanol, ethyl alcohol, isopropyl alcohol；The esters such as ethyl acetate；Acetonitrile etc. is nitrogenous Compound；The ethers such as tetrahydrofuran；Water etc..These can be used alone, and can also be used in combination of two or more.

Total amount as the usage amount of above-mentioned solvent, relative to DL-AP or its hydrate and alkaline optically active compound For example, 1~100 weight % or so.When the usage amount of solvent is more than above range, the concentration of reacted constituent is reduced, and has reaction speed Spend the tendency of decline.

As reaction atmosphere, as long as reaction is not hindered to be not particularly limited, such as air atmosphere, nitrogen gas can be Any one of atmosphere, argon atmosphere etc..

Reaction temperature is, for example, 0~100 DEG C or so.Reaction time is, for example, 1~10 hour or so.In addition, reaction can be with It is carried out with method either in intermittent, semibatch, continous way etc..

Hereinafter, to use amino acid (D-Bs or L-Bs) as in case where alkaline optically active compound (Bs), To illustrate that (especially diastereoisomeric salt mixes the manufacturing method of optically active 2- amino-phosphonoalkyl hydrochlorate of the invention The fractional crystallization method of object).In the alkaline optically active compound other than using amino acid, also so.

The salt or its hydrate and L-AP and L of D-AP contained in diastereomer salt mixture and L body (L-Bs) The salt or its hydrate of body (L-Bs) are different from each other relative to the solubility of solvent, the salt or its water of D-AP and D body (D-Bs) Salt or its hydrate for closing object and L-AP and D body (D-Bs) are also different from each other relative to the solubility of solvent.Therefore, may be used By easily that a kind of diastereoisomeric salt is isolated using the fractional crystallization of dissolubility difference.

And there is following tendency: the crystallinity ratio L-AP and L body of the salt or its hydrate of D-AP and L body (L-Bs) (L-Bs) salt or its hydrate is excellent, the crystallinity ratio D-AP and D body of the salt or its hydrate of L-AP and D body (D-Bs) (D-Bs) salt or its hydrate is excellent.Thus, for example, making L body (L-Bs) and DL-AP hydrate reaction, then D- is obtained The salt or its hydrate and the salt of L-AP and L body (L-Bs) or the mixture of its hydrate of AP and L body (L-Bs) are (diastereomeric Body salt mixture), the salt or its hydrate of the D-AP and L body (L-Bs) in diastereomer salt mixture made is first with crystalline substance Body form be precipitated, carried out for filtration treatment it is isolated, will be contained in the filtrated stock by filtrated stock for resolution process The salt or its hydrate transformations of L-AP and L body (L-Bs) are L-AP hydrate, the L- for then making D body (D-Bs) and obtaining AP hydrate reaction is precipitated the salt of thus obtained L-AP and D body (D-Bs) or its hydrate with crystal form, thus may be used With the salt or its hydrate of isolated D-AP out and alkaline optically active compound respectively and L-AP and alkaline optical activity Close the salt or its hydrate of object.

In addition, be not particularly limited as the method precipitated crystal, can be suitable for using known customary way, such as Crystallisation by cooling, lean solvent crystallization, evaporative crystallization, piezocrystallization etc..

An example of the manufacturing method of optically active 2- amino-phosphonoalkyl hydrochlorate of the invention described below.As The DL-AP hydrate that raw material uses is expressed as " DL-APnH₂O " (n represents more than 0 and 5 numbers below).In addition, (t- 1), (t-2), (t-3) are identical or different, indicate 0~5 number.

[changing 11]

According to the present invention, as diastereoisomeric salt, can efficiently and high-purity it is isolated go out following formula (1-1 '-B) Shown in, shown in D-2- amino-phosphono alkanoic acid or its hydrate and following formula (1-2 '-B), L-2- amino- Phosphonoalkyl hydrochlorate or its hydrate.

[changing 12]

(in formula, m ' indicates 1,3 or 7, and t indicates 0~5 number.Bs indicates alkaline optically active compound, and (wherein, optics is living Except property lysine).* asymmetric atom is indicated)

[changing 13]

(in formula, m ' indicates that 1,3 or 7, t ' indicate 0~5 number.Bs indicates alkaline optically active compound (wherein, optics Except REACTIVE LYSINE).* asymmetric atom is indicated)

As D-2- amino-phosphonoalkyl hydrochloride hydrates shown in above-mentioned formula (1-1 '-B),

When m '=1, alkaline optically active compound is preferably selected from chinidine, cinchonidine, L-arginine, D- to hydroxyl Compound in base phenylglycine hydrazides and D- phenylalanyl amine.

When m '=3, alkaline optically active compound is preferably l-tyrosine hydrazides.

When m '=7, alkaline optically active compound is preferably selected from L- leucinol and (R) -2- amino-n-butyl alcohol In compound.

As L-2- amino-phosphonoalkyl hydrochloride hydrates shown in above-mentioned formula (1-2 '-B),

When m '=1, alkaline optically active compound is preferably selected from the compound in cinchonine and L-Orn.

When m '=3, alkaline optically active compound is preferably selected from (R) -1- phenylpropylamine, L- valerian ammonia alcohol, D- pairs Hydroxyphenyl methyl esters, D- phenylalanyl amine, D-HPG hydrazides and the sweet ammonia of D- p-hydroxybenzene Compound in acetoacetic ester.

When m '=7, alkaline optically active compound is preferably selected from d-glucosamine, L- valerian ammonia alcohol, (R) -1- phenyl Compound in ethamine and D-HPG hydrazides.

(especially by optically active 2- amino-phosphonoalkyl hydrochlorate (including hydrate) obtained by the above method Shown in D-2- amino-phosphono alkanoic acid or its hydrate shown in above-mentioned formula (1-1 '-B) and above-mentioned formula (1-2 '-B) L-2- amino-phosphonoalkyl hydrochlorate or its hydrate) non-hygroscopic at room temperature, excellent storage stability, therefore be easy to locate Reason.In addition, not having cytotoxicity, safety is excellent.In addition, having pharmacological activity same as NAHLSGEN (such as collagen Generate facilitation effect, glutathione generates facilitation effect, wound repair facilitation effect), the barrier function of skin is improved, inhibits to become The former intrusion of state reaction, can inhibit allergy.Thus, for example, can be suitable for for purpose is treated or prevented The skin diseases such as quick dermatoses, ichthyosis vulgaris, senile xerosis.Furthermore it is also possible to as oral mucosa, eye mucous membranes Deng cell migration promotor and the treatment for the eye mucous membranes disease such as be suitable for the diseases of cari oris mucosa such as periodontosis, conjunctivitis or Prevention.

It should be noted that can for example pass through non-patent literature as the DL-AP of raw material or its hydrate [Kosolapoff G.M.Isomerization of alkyl phosphites.VII.Some derivatives of 2- Bromoethanephosphonic acid J.Am.Chem.Soc.1948,70,1971-1972；Chambers,J.R., Isbell, A.F.A new synthesis of amino phosphonic acids.J.Org.Chem.1964,29,832- 836] method recorded in manufactures.

More specifically, it can be manufactured via reaction shown in following formula.In following formula, m indicates 1~7 integer, n Represent more than 0 and 5 numbers below.X indicates halogen atom (fluorine atom, chlorine atom, bromine atom or iodine atom), R, R ' it is identical or not Alkyl that is same and indicating carbon number 1~10.The protecting group of R " expression amino.DPR indicates the deprotection for the amino protected by protecting group Agent.* asymmetric atom is indicated.It should be noted that the protecting group as amino, it can be mentioned, for example the alkyl of: carbon number 1~10, Aralkyl, the acyl group (R of carbon number 7~18¹C (=O) base；R¹For the alkyl of carbon number 1~10), alkoxy carbonyl (R²OC (=O) base； R²For the alkyl of carbon number 1~10), the benzyloxycarbonyl that can have substituent group, the phenylmethylene that can have substituent group, can have The diphenylmethylene etc. of substituent group.In addition, as above-mentioned substituent group, it can be mentioned, for example: the alcoxyl of halogen atom, carbon number 1~3 Base, nitro etc..

[changing 14]

The reaction of above-mentioned [1] be phosphite ester shown in formula (3) reacted with alkylene dihalide shown in formula (2) and Obtain the reaction (Michaelis-Arbuzov Reaction) of phosphono alkanoic acid shown in formula (4).Shown in above-mentioned formula (3) The usage amount of phosphite ester is, for example, 0.1~1.0 mole or so relative to 1 mole of alkylene dihalide shown in formula (2).

The reaction temperature of the reaction of above-mentioned [1] is preferably, for example, 130~140 DEG C or so.Reaction time is, for example, 0.5~2 Hour or so.

The reaction of above-mentioned [2] be formula (5) compound represented with via shown in formula (4) obtained from the reacting of [1] Phosphono alkanoic acid is reacted, to obtain the reaction of formula (6) compound represented.Above-mentioned formula (5) compound represented makes Dosage is, for example, 0.7~1.3 mole or so relative to 1 mole of phosphono alkanoic acid shown in formula (4).

From the effect aspect for being promoted reaction progress, the reaction of above-mentioned [2] preferably carries out in the presence of a base.As Above-mentioned alkali, it can be mentioned, for example: carbonates (the especially carbon of alkali metal such as saleratus, sodium bicarbonate, potassium carbonate, sodium carbonate Barbiturates)；The hydroxide of the alkali metal such as sodium hydroxide, potassium hydroxide；The hydrogen-oxygen of the alkaline-earth metal such as calcium hydroxide, magnesium hydroxide Compound；The phosphoric acid salts such as sodium dihydrogen phosphate, potassium dihydrogen phosphate (the especially phosphoric acid salt of alkali metal)；Sodium acetate, potassium acetate etc. Metal carboxylate (the especially metal carboxylate of alkali metal)；The organic bases such as triethylamine, pyridine；The metals alcohol such as sodium methoxide, sodium ethoxide Salt (especially alkali alcoholate class)；Metal hydrides species such as sodium hydride etc..These can be used alone, Huo Zheke To be used in combination of two or more.The usage amount of alkali is, for example, 0.9~1.1 relative to 1 mole of phosphono alkanoic acid shown in formula (4) Mole or so.

The reaction of above-mentioned [2] is preferably carried out in the presence of a solvent.As above-mentioned solvent, it can be mentioned, for example: acetone, ethyl The ketones such as methyl ketone；The ethers such as tetrahydrofuran, dioxanes；The nitriles such as acetonitrile；The sulfoxide types such as dimethyl sulfoxide；The sulfones such as sulfolane Class；The esters such as ethyl acetate；The amides such as dimethylformamide；The alcohols such as methanol, ethyl alcohol, the tert-butyl alcohol；Pentane, hexane, petroleum The hydro carbons such as ether；Benzene,toluene,xylene etc. is aromatic hydrocarbon；Halogen-containingization such as methylene chloride, chloroform, bromofom, chlorobenzene, bromobenzene Close object；The linear carbonates such as dimethyl carbonate, diethyl carbonate, methyl ethyl carbonate；The ring-types such as ethylene carbonate, propylene carbonate Carbonic ester etc..These can be used alone, or can be used in combination of two or more.

The reaction temperature of the reaction of above-mentioned [2] is preferably, for example, 100~110 DEG C or so.Reaction time is, for example, 6~24 small When or so.

The reaction of above-mentioned [3] is being protected by protecting group for formula obtained from the reaction made via [2] (6) compound represented Carboxyl (- COOR '), by protecting group protect amino (- NHR ") and by protecting group protect phosphonic acid base (- P (=O) (OR)₂) deprotection obtain the reaction of formula (7) compound represented.It can be passed through by the deprotection for the group that protecting group is protected React deprotection agent to carry out.It (is indicated in above-mentioned formula with " DPR ") as above-mentioned deprotection agent, can be suitable for using strong Alkali (such as sodium hydroxide) or strong acid (such as hydrochloric acid).

The reaction temperature of the reaction of above-mentioned [3] is preferably, for example, 90~100 DEG C or so.Reaction time is, for example, 20~24 small When or so.

The reaction of above-mentioned [4] is to make have the function of that the compound for capturing deprotection agent is obtained with via reacting for [3] Formula (7) compound represented reaction and capture deprotection agent, to obtain the reaction of formula (1) compound represented.Such as , it is preferable to use propylene oxide is as the compound with capture deprotection agent in the case that deprotection agent is hydrochloric acid.Tool Play the role of capturing the usage amount of the compound of deprotection agent relative to 1 mole of compound represented of formula (7) be, for example, 3.0~ 6.0 moles or so.

Formula (1) compound represented hydrate (=formula (1') compound represented, the n in formula represent more than 0 and 5 with Under number) can be as will be made via (1) compound represented of formula obtained from the reaction of [4] for the process of above-mentioned [5] It makes.Specifically, by the crystallization treatment by formula (1) compound represented for using water and water-soluble solvent, so as to obtain To formula (1') compound represented.

As above-mentioned water-soluble solvent, the organic solvent preferably dissolved under room temperature (25 DEG C) with water with arbitrary ratio, It is preferred that being the organic solvent of 50% or more (preferably 80% or more, particularly preferably 95 or more) to the solubility of water.

As above-mentioned water-soluble solvent, it is preferable to use alcohol (such as lower alcohol of the carbon numbers such as methanol, ethyl alcohol 1~5).

The atmosphere of reaction as above-mentioned [1]~[5] can be for example as long as reaction is not hindered to be not particularly limited Any one of air atmosphere, nitrogen atmosphere, argon atmosphere etc..In addition, reaction can carry out under normal pressure, decompression or pressurization. In addition, reaction can be carried out with method either in intermittent, semibatch, continous way etc..

Above-mentioned [1]~[5] it is each after reaction, obtained reaction product implementation can be for example filtered, washed, be done Dry (such as natural drying, reduced vacuum drying, heated-air drying etc.) etc..

[manufacturing method of optically active 2- amino-phosphono alkanoic acid or its hydrate]

The manufacturing method of optically active 2- amino-phosphono alkanoic acid or its hydrate of the invention is characterized in that, Optically active 2- amino-phosphine is obtained in the manufacturing method by above-mentioned optically active 2- amino-phosphonoalkyl hydrochlorate After acyl group alkyl salt (including hydrate), decomposed, obtain it is with steric configuration identical with above-mentioned compound processed, Corresponding optically active 2- amino-phosphono alkanoic acid or its hydrate.

As optically active 2- amino-phosphonoalkyl hydrochlorate (including hydrate) decomposition method, do not limit especially Determine, it is preferable to use ion exchange resin (especially acid cation exchange resin).As ion exchange resin, can be used for example Trade name " Amberlite IR-120B " (Organo Co. Ltd. system), trade name " Diaion " (Mitsubishi Chemical's (strain) system) Deng.

After optically active 2- amino-phosphonoalkyl hydrochlorate (including hydrate) decomposes, obtained reaction product is excellent Choosing is implemented such as being filtered, washed, dry.

Using the above method, high-purity can be obtained, and (optical purity is, for example, 99.0%e.e. or more, preferably 99.5% E.e. above, particularly preferably 99.9%e.e. or more) D-AP or its hydrate or L-AP or its hydrate.

According to the present invention, efficient and high-purity D-2- amino-shown in following formula (1-1 ') especially can be obtained L-2- amino-phosphonoalkyl acid hydrate shown in phosphonoalkyl acid hydrate or following formula (1-2 ').

[changing 15]

(in formula, m ' indicates 1,3 or 5, and n represents more than 0 and 5 numbers below.* asymmetric atom is indicated)

[changing 16]

(in formula, m ' indicates 1,3 or 5, and n represents more than 0 and 5 numbers below.* asymmetric atom is indicated).

[salt of optically active body, optically active body and alkaline optically active compound]

It is living by optically active 2- amino-phosphonoalkyl hydrochlorate (including hydrate) obtained by the above method, optics 2- amino-phosphono alkanoic acid (including hydrate) of property is without hygroscopy, crystallization at room temperature.Therefore, storage stability is excellent It is different, it can keep within 6 months or more (especially 24 months or more) stablizing in the environment of room temperature, relative humidity 75%, be easily handled. Moreover, having the pharmacological activity with NAHLSGEN (registered trademark) equally or above.For example, if by above-mentioned optical activity 2- amino-phosphonoalkyl hydrochlorate (including hydrate), 2- amino-phosphono alkanoic acid (including hydrate) (10 μM or so) Human skin fibroblasts are delivered medicine to, then obtain the effect for keeping the generation of collagen hyperfunction.In addition, the generation of above-mentioned collagen is in concentration Occur to dependence hyperfunction, even if overdose, the generation of collagen will not be unlimitedly hyperfunction.Further, it is also possible to play Elastin laminin generates facilitation effect, HSP47 generates facilitation effect, glutathione generates facilitation effect, filaggrin produces Raw facilitation effect, filaggrin gene expression facilitation effect, skin epidermis keratinocyte migration proliferation rush Into effect, wound repair facilitation effect etc..In addition, not having cytotoxicity, safety is excellent.Therefore, it can be used as collagen production Raw promotor, elastin laminin generate promotor, HSP47 generates promotor, glutathione generates promotor, filaggrin Generate promotor, filaggrin gene expression promotor, skin epidermis keratinocyte migration proliferation promotion The suitable use such as agent.Furthermore it is also possible to as oral mucosa, eye mucous membranes etc. cell migration promotor and be suitable for periodontal The treatment or prevention of the eye mucous membranes disease such as the diseases of cari oris mucosa such as disease, conjunctivitis.

Above-mentioned optically active 2- amino-phosphonoalkyl hydrochlorate (including hydrate), 2- amino-phosphono alkanoic acid (including hydrate) be suitable for using skin, hair beauty health-care as the purposes of target.Furthermore, it is possible to for treatment, prevention Purpose and be suitable for collagen, elastin laminin, HSP47, glutathione, filaggrin, skin epidermis angling The migration of cell is proliferated related various diseases.

By above-mentioned optically active 2- amino-phosphonoalkyl hydrochlorate (including hydrate), 2- amino-phosphonoalkyl When sour (including hydrate) is used for crust (skin, hair, nail etc.), it can obtain promoting the generation of collagen, improve barrier function Effect.Thus, for example, it is dermopathic to be suitable for anaphylaxis dermatosis, ichthyosis vulgaris, senile xerosis etc. It treats or prevents.In addition, working as above-mentioned optically active 2- amino-phosphonoalkyl hydrochlorate (including hydrate), 2- amino- When phosphono alkanoic acid (including hydrate) is used for skin, by promoting the generation of glutathione, the generation of filaggrin, To which antiageing effect, whitening effect can be obtained.Therefore, the additive that can suitably apply some make up etc. as skin care uses.

It applies some make up as above-mentioned skin care, it may for example comprise: foundation cream, eye shadow, mascara, eyebrow pencil, blush, lipstick, nail polish Etc. basic cosmetics such as makeup cosmetics, toner, lotion, beautifying liquid etc..

Above-mentioned optically active 2- amino-phosphonoalkyl hydrochlorate (including hydrate), 2- amino-phosphono alkanoic acid The additive amount of (including hydrate) can be suitable for depending on the application adjustment.For example, concentration when being added to cosmetics is, for example, to reach The range of 0.5~70 μM (preferably 10~60 μM, particularly preferably 30~60 μM, most preferably 40~60 μM).