JPH1077290A - Diazacyclophosphamide derivative effective in determining optical purity and steric configuration of amines and alcohols - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new derivative, comprising any one of optical isomers of a specific diazacyclophosphamide chloride derivative and useful as a reagent, etc., for determining the optical purity and steric configuration of optically active amines or alcohols. SOLUTION: This new diazacyclophosphamide derivative is any one of optical isomers of a diazacyclophosphamide chloride derivative represented by formula I [Ar is a (substituted)aromatic group] and is useful as a reagent, etc., effective in determining the optical purity and steric configuration of amines or alcohols having the asymmetric center by using a heteroatom nuclear magnetic resonance (NMR) according to the measurement of<31> P-NMR for the optical purity with attention paid to phosphorus atom at 100% natural abundance ratio and according to<1> H-NMR for the steric configuration. The compound is obtained by reacting a (2S)-substituted anilinomethylpyrrolidine represented by formula II (Ph is phenyl) or a (2R)-substituted anilinomethylpyrrolidine represented by formula III with phosphorus oxychloride in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION Determining the steric configuration or optical purity of a natural product or a compound having a complex molecular structure having various functional groups such as amino groups and hydroxyl groups involved in the molecule in the molecule is a synthetic chemistry. It has very important significance. The present invention relates to any one of optical isomers of a diazacyclophosphamide chloride derivative which is extremely useful for determining the configuration or optical purity of such a compound, a method for producing the same, and an optically active diazacyclophosphamide chloride. It is an object of the present invention to provide a method for determining the optical purity and configuration of an amine or alcohol having an asymmetric center using a amide derivative.

[0002]

2. Description of the Related Art As a method for determining the optical purity and configuration of an amine or alcohol having an asymmetric center, M
(S)-or (R) -α-methoxy-α-trifluoromethylphenylacetic acid (MTP) developed by Osher et al.
A method using A) for determination in nuclear magnetic resonance (NMR) measurement has been known. That is, regarding the optical purity and configuration determination of protic compounds such as primary amines and secondary alcohols having an asymmetric center,
The above (S)-or (R) -MTPA is reacted with a protic compound to lead to an amide or ester derivative. The steric configuration is determined by ¹ H-NMR measurement, and the optical purity is determined by ¹⁹ F-NMR measurement. I was

[0003]

However, the above method is an excellent method, but has the following problems. (A) MTPA is not synthesized in large quantities and must be optically resolved during the manufacturing process. (B) Commercially available reagents for (a) are costly.

The present invention focuses on a phosphorus atom having a natural abundance ratio of 100% from the background that polynuclear NMR has become widely used, uses ³¹ P-NMR measurement for optical purity, and uses ¹ P-NMR measurement for steric configuration. The present invention provides an effective reagent for determining the optical purity and the configuration of an amine or alcohol having an asymmetric center using H-NMR.

[0005]

Hereinafter, the present invention will be described in detail. The present invention relates to any one of the optical isomers of the diazacyclophosphamide chloride derivative represented by the general formula (I), which is extremely useful for determining the configuration or optical purity of an amine or alcohol having an asymmetric center. The present invention relates to a species, a method for producing the same and a method for determining the optical purity and configuration of amines and alcohols having an asymmetric carbon using these optically active diazacyclophosphamide derivatives.

[0006]

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The optical isomers of the diazacyclophosphamide chloride derivative represented by the general formula (I) include four types of isomers (a) to (d) shown in Chemical Formula 5.

[0008]

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The present invention provides the following (2)
S) or (2R) -anilinomethylpyrrolidine is reacted with phosphorus oxychloride in the presence of a base to give a diazacyclophosphamide derivative (where Ar is an alkyl group such as a methyl group, halogen such as a chlorine atom, etc.) A phenyl group or a naphthyl group which may have a substituent such as an atom or an alkoxy group such as a methoxy group.) In a high yield and stereoselectively.

[0010]

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In the above reaction, the molar ratio of the reaction between anilinomethylpyrrolidine and phosphorus oxychloride is preferably 1 to 3 times the molar amount of the former 1 mol.

In the above reaction, the base used is triethylamine, diethylisopropylamine,
Pyridine, organic bases such as 1,8-diazabicyclo [5,4,0] undecene, alkali metal or alkaline earth metal hydrides such as sodium hydride and calcium hydride, carbonates such as sodium carbonate and potassium carbonate,
Bicarbonate such as sodium bicarbonate, potassium t-
Examples thereof include alcoholates such as butoxide and sodium ethoxide, and organic lithium such as butyllithium. Among them, an organic base such as triethylamine is particularly preferably used.

The above reaction is carried out in the presence or absence of a suitable inert solvent. Examples of the solvent used include ethers such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, aromatic hydrocarbons such as toluene, benzene and xylene, and saturated hydrocarbons such as n-hexane, n-heptane and cyclohexane. And esters such as ethyl acetate, and amides such as N, N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The above reaction proceeds smoothly at a temperature ranging from −78 ° C. to the boiling point of the solvent.

The obtained optically active diazacyclophosphamide derivative can be reacted with a racemic amine in the presence of triethylamine to convert it into a phosphamide derivative (see Chemical Formula 7).

[0015]

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In the case of racemic alcohols, the alcohols are converted into lithium alkoxides by the action of alkyllithium such as n-butyllithium and then reacted with a diazacyclophosphamide derivative to give the corresponding phosphamide. It can be converted to a derivative (see Chemical formula 8).

[0017]

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The configuration and optical purity of the obtained phosphamide derivative can be easily determined from ¹ H and ³¹ P-NMR spectra.

[0019]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in more detail with reference to embodiments. Example 1 Synthesis of (2S, 5S) -2-chloro-3-phenyl-2-phospha-1,3-diazabicyclo [3.3.0] heptane-2-oxide ( 2 ) (2S) -anilinomethyl 0.50 g of pyrrolidine ( 1 )
(2.8 mmol) and 0.60 g of triethylamine
(6.0 mmol) of dry tetrahydrofuran (10 m
l) Cool the solution to -78 ° C and add phosphorous oxychloride 0.43
g (2.8 mmol) of tetrahydrofuran (5 ml)
The solution was added dropwise. After stirring at the same temperature for 2 hours, the temperature was slowly returned to room temperature. Triethylamine hydrochloride of the generated precipitate was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain 0.7 g (yield 95.2%) of the compound (2) as crystals. ^{From the 31} P-NMR measurement, the target compound ( 2 ) and (2S, 5)
S) -2-Chloro-3-phenyl-2-phospha-1,
The formation ratio of 3-diazabicyclo [3.3.0] heptane-2-oxide ( 3 ) was ( 2 ) / ( 3 ) = 92/8. The crude product (2S, 5S) -2-chloro-
0.5 of 2-phenyl-2-phospha-1,3-diazabicyclo [3.3.0] heptane-2-oxide (2)
g of chloroform / n-hexane (10/5 = v / v)
Recrystallized. At this stage 0.4 g of almost optically pure compound ( 2 ) was obtained and the isomer ( 3 ) was removed.
Further, the crude product of ( 2 ) could be separated and purified by column chromatography (developing solution: ethyl acetate / n-hexane (10/1 = v / v)). mp 117-118 ° C. [α] _D + 117.3 ° (c
0.80, CHCl _3). Compound ¹ H-NMR analysis results concerning the (2) shown in Table 1 below.

[0020]

[Table 1]

In the synthesis of the compound ( 2 ), the formation ratio of ( 2 ) and ( 3 ) was 9/91 under the condition of a reaction temperature of 0 ° C. The configuration at the phosphorus atom of the compound ( 3 ) was determined by single crystal X-ray structure analysis. (See Table 1 and Chemical Formula 9).

[0022]

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Example 2 Synthesis of (2R, 5R) -2-chloro-3-phenyl-2-phospha-1,3-diazabicyclo [3.3.0] heptane-2-oxide ( 5 ) As a starting material, Except that 2R) -anilinomethylpyrrolidine ( 4 ) was used, the conditions for the reaction and the separation and purification were the same as in Example 1 above. The formation ratio of (2R, 5R) isomer ( 6 ), which is an optical isomer of compound ( 5 ) and ( 5 ), was ( 5 ) / ( 6 ) = 8/92. mp. 117-118 ° C. [α] _D −117.4 ° (c
0.72, CHCl ₃ ). The NMR spectrum of the compound ( 6 ) is the same as that of the compound ( 3 ) in the form of an enantiomer, and thus is omitted here. Incidentally, in the synthesis of Compound (6), generating ratio of the original conditions of 0 ℃ reaction temperature (5) (6) it was 9/91.

A method for synthesizing typical phosphamide derivatives of amines and alcohols using the compounds ( 3 ) and ( 6 ) synthesized in Examples 1 and 2 will be described below. Example 3 (±) -1- using (2S, 5S) -2-chloro-3-phenyl-2-phospha-1,3-diazabicyclo [3.3.0] heptane-2-oxide ( 3 ) Determination method of optical purity and configuration of phenylethylamine (±) -1-phenylethylamine was added to a solution of 0.26 g (1.0 mmol) of compound ( 3 ) and 0.1 g (1.0 mmol) of triethylamine in 5 ml of dry tetrahydrofuran. .12 g (1.0 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The resulting precipitate of triethylamine hydrochloride was filtered, and the filtrate was concentrated under reduced pressure. The obtained syrupy residue is subjected to thin layer chromatography (developing solution;
Separation and purification with ethyl acetate), the phosphamide derivative ( 8
a, b ) 0.31 g (93.9% yield).

Optical purity determination method : The synthesized phosphamide derivative ( 8 ) was prepared as a chloroform solution or a chloroform solution in a NMR tube (arbitrary concentration) by an ordinary method. ³¹ P-NMR (85% H ₃ PO ₄ was used as an external standard. The optical purity was used in the following method) was measured by the proton decoupling method, and the diastereomer formation ratio was calculated by integrating the spectra. The ratio was determined from the ratio (for the determination of optical purity, there is no particular need for separation and purification by chromatography or the like). Table 2 shows the diastereomer ratios, chemical shift values, and chemical yields with respect to the results of the optical purity, which were compared with the results of the reaction with pure optically active amines.

[0026]

[Table 2]

Determination of steric configuration : The phosphamide derivative ( 8 ) separated and purified was prepared as a heavy chloroform solution (arbitrary concentration) in an NMR tube by a usual method. The results of ¹ H-NMR measurement of the phosphamide derivative obtained by reacting with an optically active amine and the phosphamide derivative obtained by reacting with a D, L-amine were compared. As a result, the substituents L ₁ located on the asymmetric carbon, which is estimated to be present in solution, the spectral absorption was observed upfield than L ₁ in the structure B. This is considered to be due to the shielding effect of the benzene ring of the N-phenyl group in the structure of diazacyclophosphamide ( 8 ). The substituent L
₁ and L ₂ indicates a preference to be used in determining the configuration. From the above results, the configuration of the amine in the structure A is (R), and the configuration of the amine in the structure B is (S) (see Chemical Formula 10).

[0028]

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The above results are shown in Table 1 above. The same applies to the determination of the configuration of alcohol shown below.

Example 4 (2S, 5S) -2-chloro-3-phenyl-2-phospha-1,3-diazabicyclo (3.3.0) heptane-2-oxide ( 3 ) was used (±) Method for determining optical purity and configuration of 2-octanol (±) 0.13 g of 2-octanol (1.0 mmol)
l) in dry tetrahydrofuran (10 ml)
The solution was cooled to 0.75 ml of n-butyllithium.
(1.65 M n-hexane solution) was added, and the mixture was stirred at the same temperature for 2 hours. Then, 0.26 g (1.0 mmol) of compound ( 3 ) was added.
A solution of l) in tetrahydrofuran (10 ml) was added dropwise. Thereafter, the mixture was further stirred at room temperature for 12 hours, and then heated under reflux for 1 hour. Water was added to the reaction mixture to stop the reaction, and then the reaction mixture was extracted with chloroform. The extracted organic layer was dried over anhydrous sodium sulfate and then filtered.
The filtrate was concentrated, and the residue was purified by thin-layer chromatography under the same conditions as in Example 5 to obtain the compound ( 10b, c ). Example 3 regarding determination of optical purity and configuration
Was performed in the same manner as described above.

Example 5 (2R, 5R) -2-chloro-3-phenyl-2-phospha-1,3-diazabicyclo [3.3.0] heptane-2-oxide ( 6 ) was used (±). Method for Determining Optical Purity and Configuration of -1-Phenylethylamine The reaction of compound ( 6 ) with (±) ─1-phenylethylamine, the determination of optical purity and the determination of configuration were performed under the same conditions as in Example 3. ( 9 ) was obtained. still,
Regarding the steric configuration, the relationship was opposite to that when compound ( 3 ) was used. That is, it was found that the configuration of the asymmetric carbon in structure A was (S) and the configuration of the asymmetric carbon in structure B was (R).

Example 6 (2R, 5R) -2-chloro-3-phenyl-2-phospha-1,3-diazabicyclo [3.3.0] heptane-2-oxide ( 6 ) was used (±). Method for Determining Optical Purity and Configuration of -2-Octanol The reaction with compound ( 6 ), the determination of optical purity and the determination of configuration were performed under the same conditions as in Example 6 to obtain compound ( 11 ). The same result as in Example 5 was obtained.

[0033]

As described above, according to the present invention, the following excellent effects can be obtained. (A) The chemical yield of each synthesis step is high. (B) (2R, 5S) -2-chloro-3-phenyl-2
-Phospha-1,3-diazabicyclo [3.3.0] heptane-2-oxide ( 3 ), (2S, 5R) -2-chloro-3-phenyl-2-phospha-1,3-diazabicyclo (3. 3.0) The stereoselectivity in the synthesis of heptane 2-oxide ( 6 ) is extremely high. (C) Compounds ( 3 ) and ( 6 ) are crystalline substances and are not easily hydrolyzed, so that they are easy to handle. (D) phosphamide derivative (( 8 )
( 11 )), the configuration of the phosphorus atom is completely maintained. (E) The optical purity and configuration of the synthesized phosphamide derivative can be easily determined from ¹³ P and ¹ H-NMR. (F) Compounds ( 3 ) and ( 6 ) have an aromatic ring in the molecule, and the diastereomer ratio is observed by high performance liquid chromatography since UV detection is easily performed. (G) The operation method is extremely simple. (H) Raw materials are only easily available reagents. (I) Mass synthesis, that is, industrialization is possible.

Claims (3)

[Claims] 1. An optical isomer of a diazacyclophosphamide chloride derivative represented by the general formula (I). Embedded image (In the formula, Ar represents an aromatic group which may have a substituent.) 2. A compound represented by the general formula (I) wherein (2S) -substituted anilinomethylpyrrolidine or (2R) -substituted anilinomethylpyrrolidine is reacted with phosphorus oxychloride in the presence of a base. Any one of the optical isomers of the diazacyclophosphamide chloride derivative. Embedded image 3. An optical purity of an amine or alcohol having an asymmetric carbon, wherein one of optical isomers of a diazacyclophosphamide chloride derivative represented by the general formula (I) is used. And a configuration determination method. Embedded image (In the formula, Ar represents an aromatic group which may have a substituent.)