JPS58116493A - Novel phosphine amide compound and manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel phosphinamide compound and a novel method for producing the same.

The invention further relates to the use of phosphinamides for the preparation of various compounds of phosphorus, of particular interest being phosphinates.

A significant advantage of the present invention is the ability to produce a variety of optically active compounds in high yield and high optical purity.

The use of organic compounds containing phosphorus, especially optically active compounds,
Well known now.

Many natural and synthetic compounds have been developed using transition polymetal catalysts, especially catalysts consisting of optically active organophosphorus ligands.
It is currently known that they can be produced by asymmetric synthesis.

In this way, substances of interest in the agricultural, food, pharmaceutical and perfumery fields are produced. One example is L-DOPA, which is particularly useful in treating Parkinson's disease.

However, the development and research of such production methods is currently limited due to the difficulty in producing optically active organophosphorus ligands, which are most often used as asymmetric catalysts.

Therefore, the present invention aims to improve the production technology of optically active organophosphorus ligands, and aims to produce a series of organophosphorus compounds, particularly phosphinamides, and phosphinates, phosphine oxytos, phosphines, phosphoniums, and phosphines derived from the phosphinamides. It provides an easier and more economical method of manufacturing imides and the like.

By using phosphinate as a starting material, various compounds such as those mentioned above can be easily obtained. Therefore, it is important to produce phosphinates in a more economical manner than previously available.

Traditional phosphinate production methods have been quite labor intensive.

Namely, Mislow et al. (1999) et al. started from dichlorophosphine and separated it into two types of phosphinate via menthylphosphinate, but the entire process consisted of seven steps. (Journal of the American Chemical Society, J. Am.

Chem, Soc, 91, 7393 (19
69) and Journal of the Organic Chemistry.

J, Org, Chem, 37, 2272
(1972)).

Another route for the production of optically active phosphinates uses 1,3,2-oxoazaphosphole as the starting material (tetrahedron letter).

Tetrahedron, I, et, , 571
, (1980)).

However, this method also requires separation into two oxoazaphospholes and the use of organometallic reagents, and the entire procedure consists of four steps.

In general, currently used methods provide low yields of phosphinate, are lengthy steps, require difficult resolution into two intermediates, and have two desirable phosphinate substituents. requires the use of key intermediate compounds available in

In such a manufacturing method, the choice of the third substituent of the phosphinate is limited.

The novel method for producing phosphinates of the present invention utilizes a one-step reaction of phosphinamide and enables the production of all desired phosphinates by alcoholysis, and is carried out easily and economically. be able to.

The preparation of phosphinamides according to the invention can be carried out very rapidly, ie in 15 minutes, and with industrially acceptable yields. This reaction can also be allowed to proceed more slowly to achieve higher yields.

Generally, about 1 hour is sufficient to convert the phosphinamide to the corresponding phosphinate.

The intermediates of this process have good chemical stability and do not require complex reagents or reactions and harsh operating conditions.

Other substantial advantages for the production of optically active compounds are:
It is possible to introduce asymmetricity with extremely high purity.

The method for producing phosphinamide according to the present invention comprises organic...
The process involves the action of a halogenide on oxoazaphospholidine, and is characterized by the fact that it is carried out in the absence of air, humidity, and light. This reaction is represented by the following reaction formula (1).

(A) (8) (O In the above reaction formula, symbols R1 and R3-R7 represent a hydrocarbon group or a hydrogen atom.

These hydrocarbon groups are the same or different and are in particular aliphatic, cycloaliphatic and/or aryl. Preferably, R3 and/or a hydrogen atom.

R1, and RB,...R? Among the substituents, the most common are C1-C4 alkyl, phenyl and benzyl groups.

However, it may also be, for example, C1-CI8 alkyl, cyclopentyl, cyclohexyl, alkyl-substituted phenyl, and naphthyl.

R2 is alkyl, aralkyl, cycloalkyl, aryl, or a saturated hydrocarbon having a functional group such as ester, ether, or ketone.

According to one operational aspect of the present invention, the oxoazaphospholidine (A in formula (1) above) is collected in solid form and the alkyl, cycloalkyl or aryl halide in liquid form (A in the above formula (1)
1) Heated together with B) in equation. The phosphinamide (Q) formed is crystallized from a suitable solvent or isolated as an oil.

It is particularly surprising that this new reaction, which gives phosphinamides in suitable yields, has not been previously realized to give such results.

In fact, the authors who attempted the reaction in toluene or other solvent solutions only obtained polymers and products that were difficult to identify. [Arbuzov et al., Aka
d, Nauk, 5SSP otd Kim.

Nauk, 789, 1952) or Mukaiyama et al., Journal of the Chemical Society of Japan 13ull, Chem, SO
C, Jap, 40147.

(1967)). In contrast, in the present invention, a phosphine amide can be obtained in good yield by reacting oxoazaphospholidine with an organic halide in the absence of humidity, oxygen, and light.

When the temperature is in the range of about 40°C to about 100°C, the reaction produces phosphinamide more or less rapidly. When reacted at lower temperatures, such as for example 10-40°C, and especially at ambient temperatures between 15-30°C, the reaction is slower, but the yield and purity are better.

According to a first aspect of the invention, a solid oxoazaphospholidine prisoner is heated to the desired temperature in the dark in an inert gas with exclusion of moisture. To this an appropriate organic halide (B), R2X, is added in excess and heating is then continued for the required time.

Finally, phosphinamide (C) is obtained in a yield of 60% level, which is very good compared to known methods.

According to another embodiment of the invention, the oxoazaphospholidine and the organohalide are first dissolved in a suitable solvent, and then this solution is dissolved in a dark place under an inert atmosphere, protected from moisture, to a maximum amount of phosphine. The desired temperature is maintained until the amide is obtained.

A variety of common solvents are suitable, including aromatic, aliphatic, cycloaliphatic hydrocarbons, and the like. Particularly useful are mixtures of benzene hydrocarbons and alicyclic hydrocarbons.

The starting material, oxoazabosporidine (4), is a substance that can be easily obtained in good yield by known methods, in particular by the action of diaminobosphin and an amino alcohol.

For example, the method described by Chiruaki Mukaiyama and Yasuto Kodaira [Journal of the Chemical Society of Japan (BuJJ,
Chem, Soc, Japan) 39 (6)
1287-301 (1966)), 1,
3.2-Oxoazaphospholidine can be obtained by the reaction of diaminobosphine with an amino alcohol, in this case ephedrine. This reaction is diagrammatically expressed as shown in equation (2) below.

■ An unexpected advantage of the present invention is that if an optically active amino alcohol is used, the diastereomer of oxoazaphospholidine is converted into a diastereomer by the reaction shown in formula (2) above. Starting from lysine, bosphinamide (C) having very good diastereomeric purity can be obtained by the action of halide a3).

Thus, using (-)ephedrine as the amino alcohol, a single species of possible diastereomers of oxoazabosporidine can actually be produced, and the absolute configuration for the phosphorus atom is determined.

Regarding possible transformations of the phosphinamide obtained by the method of the present invention, the most important one is that it can be easily converted into the corresponding phosphinate by alcoholysis, as shown in formula (3) below.

(Margin below this page) (C) +R80H-+R80-PI River 1+ +u R'
(3) M20 (g) According to the method of this invention, desired groups R1, R2 and R8 can be selected for a desired phosphinate (g).

In fact, N
8 depends on the choice of alcohol or phenol used in the alcoholysis of reaction formula (3).

According to the invention, a special method for carrying out the alcoholysis is to carry out the reaction catalyzed by an ion exchange resin. This method has the advantage that the catalyst can be easily separated by simple filtration after alcoholysis.

As mentioned above, the advantage of being able to produce phosphinamide (Q) from the optically active oxoazaphospholidine prisoner is that the above (
3) It can be reflected in the production of phosphinate according to the formula. In fact, within the scope of the present invention it is possible to obtain phosphinates of the following formula (4), which correspond to the two known diagonals of absolute coordination.

According to the convention in displaying the above equation (4), R2 is located at the top (on the front side) of the page, R' is located at the bottom (on the back side) of the page, and 0 and OR' are located on the page.

The enantiomer of the absolute configuration R or S that determines the phosphinate ■ can be obtained by using the (+) or (-) amino alcohol, respectively, in formula (2) to produce the oxoazabosporidine.

Alternatively, it can also be obtained by introducing the groups R1 and R2 in a different order.

The formulas shown in the table below illustrate such possibilities.

The production of oquinazaphospholidine by the above reaction formula (2) and the conversion of phosphinamide of the formula (3) to a phosphinate by alcoholysis are already known, but these two reactions and the reaction of the present invention (formula 11) The combination of the reactions forms a very interesting three-step process to obtain phosphinates.

Due to the compounds used, the yield of each of these steps is approximately 6
The reaction time for the reaction formula (2) is approximately 12 hours, the reaction formula (1) is A time, and the reaction formula (
3) is 1 hour.

(Margins below this page) Neto →- cr3 Tadashi +
+Country
Ujimasa
Examples of the present invention are shown below. Note that these Examples do not limit the present invention.

Example 1 Because oxoazaphospholidines are important in making phosphinamides according to the present invention, one method for making one of these phospholidines was modified to (+)3,4-dimethyl-2,5
-diphenyl-1,3,2-oxoazaphospholidine (
2R, 48, 5R) is shown below as an example.The above compound [F] is a compound of the reaction formula (1) described above, in which R1 and R4 are phenyl%, R3 and R5 are hydrogen atoms, On the other hand, R6 and R7 are methyl.

This compound is a new compound that has not been previously described in the technical literature.

The production of this compound is carried out in a 3-day flask equipped with a stirrer and two nozzles: one for blowing nitrogen gas, and one for draining.

The amine thus separated during the reaction is removed from the reaction medium and collected in a wash flask.

0.1 mole (-)ephedrine total 0.1 mole bis(
diethylamino)-phenylphosphine 5o.

rrLl in toluene for 12 hours, 100 in nitrogen stream
The reaction was carried out at ~110°C. Thereafter, the reaction mixture was transferred to an evaporation bottle and the amount of solvent was adjusted to about 250 ml.

By simply cooling under a nitrogen atmosphere, the above-mentioned compound [F] precipitated out of solution. Additional portions of the compound were recovered by partially evaporating the mother liquor after evaporation.

The overall yield of crystalline compound [F] was 70%, which melts at 100'C and can be recrystallized from toluene.

Stored in a sealed container in the refrigerator. NM of the crude product obtained
The R spectrum showed very good chemical and diastereomeric purity.

The following nocilimeters were discovered.

NMR'H(CaDa) Duplex #(3H)
0.5 (ppm) doublet (3H) 2.4 multiplet (IH) 3. multiplet (IH) 5.4 multiplet (IOH), 7.7~8 NMR (C11D6) 3'P ・-・-・・-δ=
+, 139.7 pI) mNMR (THF) 31P・
・・・・・・・・・・・・δ= + 141.6 ppm
Elemental analysis values: C-chi H-chi N-chi O-chi P-chi Theoretical value 70.846.695.165.9011.42 Experimental value 70.696.665.275.6011.50
Rotating crab [α] 29'240°±5°C double, 3
(CaHa) Example 2 (-)3.4-dimethyl-2,5-diphenyl-2-oxo-1,3,2-oxoazaphospholidine (2R.

4S, 5R) production.

50 rn of oxoazaphospholidine V) 3f of Example 1
The toluene solution was left under stirring for 2 days in a flask without a stopper. After that, the toluene is evaporated,
The residue was eluted into acetone. Diisopropyl ether heated to about 50°C was then added to the solubility limit. The total volume of solvent should not be too large;
It will be about 20d. The desired oxide is precipitated by cooling. The recrystallization solvent is likewise an acetone/diimprobyl ether mixture.

If no precipitation of the product occurs, the residue obtained by the oxidation must be separated chromatographically using a silica column of the Merck type A 7734, eluent ether/acetone: 8/2. be.

The product elutes at rfQ, 7, which is generally about 100 m
This corresponds to a fraction of 1.

This method of preparation was carried out to prove the configuration of the above compound; in fact, the following oxo derivative was produced by Cooper (D
Tetrahedron Letter (Tet, Lett, ) 2697 (1
974) and its absolute configuration is known, therefore, the preparation starting from compound (1) confirms the configuration proposed for said compound [F].

The melting point of the oxo derivative was 161°C. 24 in the air
By heating for a period of time, an oxidized compound was obtained in a yield of 90%.

NMR'H (CDCj'3) Double weight (3H) 0.91 (ppm) Double line (
3H) 2.62 Multiplet (IH) 3.76 Triplet (LH) 5.76 Multiplet (IOH) 7.2~8 NMR31P (CDCl!s) δ= 33
I)I)mExample 3 (+)N-methyl-N-(1-methyl-2-iodo-2
=phenyl)-ethyl (Is, 28)P-methyl-
p-Phenylphosphineamide■.

This compound is obtained by reacting phospholidine [F] described in Example 1 with methyl iodide.

6H5 di(G) phosphinamide 0 corresponds to formula (C), R2, R6 and R7 are methyl, R1 and R4 are phenyl, R3 and R5 are hydrogen atoms, and halogen X is iodine. be.

The production of compound (G) is carried out by the following operational steps.

0.1 mol of oxoazaphosporidine [F] was heated in solid form for 10 minutes at 95-100'C under nitrogen atmosphere in a wide-mouthed filter tube. An excess of methyl iodide (0.3-0.4 mol) heated to the boiling point was added rapidly, also under a nitrogen atmosphere. Then, a substantially instantaneous reaction proceeds over a period of 5 to 1°. Upon cooling, crystals of the desired compound are obtained.

Excess iodide is easily removed by evaporation.

Regardless of whether the residue crystallizes, it is eluted with hot acetone and diisopropyl ether is added to the solubility limit. (Total volume of solvent 200 ml). Upon cooling, the desired precipitate is obtained. Yield 60%. The melting point of the product obtained was 160-162°C.

NMR'H (CDCJs): Double M (3H) 1
．． 1 (ppm) Doublet (3H) 1.95 Doublet (3H) 2.45 Multiplet (lH) 4.30 Doublet (IH) 5.15 Multiplet (IOH) 7.1-8. 20 elemental analysis values:
Cchi H person N% 0% 2% I% theoretical value: 49
．． 415.203.393.877.5030.70 Experimental value: 49.635.293.353.877.54
30.57 [α]′D +162.5°NMR”P (CDCJ3) δ: + 35.
1 ppm Example 4 (+)N-methyl-N-(1-methyl-2-iodo-2
-Phenyl)ethyl (Is, 2S) P-ethyl-P-phenylphosphineamide (2).

This is an analogue of the phosphinamide (G) of Example 3, in which the methyl bonded to the phosphorus atom of phosphinamide C) is replaced with ethyl. This compound is prepared from phospholidine [F] of Example 1 in a similar manner to Example 3, with methyl iodide replacing ethyl iodide. 7
Heat at 0°C under reflux for 8 minutes. After evaporation of the halide, the crude product of the reaction is chromatographed on alumina with ethyl acetate as eluent. 100
After 10 mJ elutions, the desired phosphine amide is recovered. The product is a thick oil. Its absolute configuration is the same as that of compound (G) described in Example 3, ie (b)p/.

As a result of the NMR (CDCJ,) test, the following was found.

Double line (3H) 1.1 (ppm) Triple line (3
H) 1.25 Triplet (3H) 2.40 Multiplet (2H) 2.10 Multiplet (IH) 4.20 Doublet (IH) 5.25 Multiplet (10H) 7.2~8.251 ) PM elemental analysis: Cchi H% Nq6 calculated value
50.60 5.43 3.28 Experimental value 50.4
8 5.54 3.24(α)” = +116°
C=5 (CHCJs) Example 5 (+)N-methyl-N-(1-methyl-2-chromium-2
-phenyl)ethyl(Is, 28)P-benzyl-P-
Production of phenylphosphineamide ■.

The target compound is a phosphine amide similar to the compound of formula (0) in reaction formula (1). That is, in formula (C), %R" is phenyl and 6!D, R2 is benzyl, and R3 is is a hydrogen atom, R4 is phenyl,
X is a bromine atom, R5 is a hydrogen atom, and R6
and R? is methyl.

Heating 0.1 mole of oxoazaphospholidine (t) of Example 1 to 90°C under nitrogen atmosphere and rapidly adding 8 moles of benzyl bromide held at this temperature under nitrogen atmosphere. Manufactured by.

The reaction proceeds in 10 minutes. After cooling and evaporation of excess benzyl bromide under reduced pressure, the residue is dissolved in hot acetone. Upon cooling, crystals of the mixture of phosphine amide diastereomers formed precipitated. It was confirmed that this halide dissipates phosphorus atoms and causes some degree of shrimping under the operating conditions described above.

After p filtration and vaporization of acetone, the residue is At20.100
The mixture was chromatographed using 4° basic alumina at a ratio of 2/D3f. The phosphine amide was obtained after 1Q times of 5Q ml elution and RMN analysis revealed the correct diastereomeric purity.

The following instructions are given for the more abundant diastereomers of the cono bond, configuration @p'.

NMR (CDCl a ) Duplex # (3H)
1.05 (ppm) double line (3H) 2.50 multiple Ill! (2H) 3.65 Multiple # (IH) 4.30 Doublet (iH) 5.05 Multiple # (15H) 7-8.2 The mixture of diastereomers separated by crystallization is heated at 180-183 °C It has a melting point of

NMR1H (CDC/3) Multiplet (IH) 3.65 Elemental analysis: 6% H Br% N% 0% P% calculated value 62.455.701B, 063.173.62
7.00 Experimental value 62.815.8017.942.8
33.767.01 [α] 2 Roux + 130” C double, 2 (CHCr3) Example 6 Preparation of a phosphine amide similar to the phosphinamide of Example 5, but having a chlorine atom in place of the bromine atom.

Production was carried out in the same manner as in the previous case. However, benzyl chloride gave a diastereomeric purity of 80/20. Crystallizing the mixture of diastereomers from acetone allows removal of most of the epimers. After evaporation of the solvent, the resulting residue was treated with basic alumina (too y
The mixture was chromatographed using an aluminum alloy (32: eluent: acetone). The diastereomers were obtained after ten 50ml elutions. The main diastereomer obtained has a p' configuration and has a melting point of 154-157°C.
It is.

NMR (CDC/3): double weight (3H) 1.05 (ppm) double line (
3H) 2.50 Multiplex (2H) 3.60 Multiplex (IH) 4.30 Double! (IH) 4.95 Multiplet (15H) 7.20 to 8.00 [α)2
0= +130°D C= 3 CHCl! s NMR3'P (CDCls
)δ=+36.34 ppm Elemental analysis: C H% Cl N 0% P calculated value 69.436.338.913.524.027
．． 78 experimental meter 68.556.438.693.434
．． The mixture of diastereomers separated by crystallization of 547.18■p + (s)p' has a melting point of 175°C. Its RMN (CDCls) is as follows.

Double weight (3H) 0.55 (ppm) Double #
(3H) 1.00 Mie M (2H) 2.50 Multiplex! (2H) 3.50 Multiplex # (IH) 4.20 Double a (IH) 4.80 Doublet (IH) 4.95 Multiplex (15H), 7.0 (1-8, 20pp
m [α几=+123” C= 1.2 CHCs NMR31P (CDCl!
3) δ=+36.47 and +36.21 ppm Example 7 Example 3 Application of the functional phosphinamide to the preparation of methylmethyl-phenyl-phosphinate, configuration R(+).

A phosphine amide of ~290 was dissolved in a 1°76N methanolic hydrogen chloride solution. After 1 hour, 10 ml of 2.8N methanolic ammonia solution was added to neutralize the acid. The solvent was evaporated and the residue was dissolved in 10111/methylene chloride and filtered to remove inorganic salts.

Evaporation of the solvent again gave a residue which was chromatographed on silica (20×20 plates) eluting with acetone. Methanol 110.5
The phosphinate formed was recovered by extracting the band between 5 and 0.650.

As a result of the RMN test at α=+52°C (500°C, showing optical purity of 93%), the structure of this boss fin was confirmed by a known document [1 Harguer (M, J, P, Harguer) Jour
n.

Chem, 5oc-Perkin I, 1294
(1979)).

Example 8 Application of the phosphinamide of Example 4 to the preparation of methyl-phenyl-phosphinate, [R(+)].

500rn9 of the phosphine amide was dissolved in 50ml of a 0.15M methanol solution of methanesulfonic acid, and the solution was left at 60°C for A time. Thereafter, it was neutralized with 100 rrLl of 4M ammoniacal solution. After evaporating the solvent, the residue was eluted with 3Qm methylene chloride and the undissolved material was filtered out. After evaporation of the solvent again, the residue was chromatographed on silica using acetone as eluent. The phosphinate formed is approximately 50 m
The eluent of 1 was collected after 10 distillations. This compound is known to be oily.

[α]0222.7゜ C-7 (methanol), optical purity = 47.

As a result of RMN, the structure described above was confirmed.

Example 9 Application of the phosphinamide of Example 6 to the preparation of methyl R(-)benzylphenyl-phosphinate.

In 50d of 0.1M methanol solution of methanesulfonic acid,
Dissolve phosphinamide 2.2f and heat the solution to 55°C.
It was kept for 2 hours. After neutralization with IM methanolic ammonia solution, the solvent was removed. The residue was eluted with methylene chloride, and after removing undissolved materials, the solvent was evaporated again. Chromatography was carried out on 50 f alumina per 21 with ethyl acetate as eluent to give the phosphinate after several elutions. The melting point of the racemate is 9
It is 6°C. Optically active phosphinate is [α), =-
3.2°, C=6 (methanol), and optical purity of 77°.

NMR (CDCl5): doublet (2H) 3.3 (ppm) doublet (
3H) 3.6 Multiweight (H) 7 to 7.8 Therefore, according to the present invention, a novel phosphinate, which has not been previously known, was obtained.

Starting from phosphinates derived from the phosphinamides obtained according to the invention, Mislow
[Journal of the American Chemical Society (J, Am.

Chem, Soc, ) 904842 (1968
) A series of phosphine oxytos were prepared by ).

In particular, the following compounds.

Benzyl methylphenylphosphine oxyto R(+)
Benzyl methylphenylphosphine oxyto 5(-)
Ethyl methylphenylphosphine oxyto R(+) Ethyl methylphenylphosphine oxyto 5(-) methyl 0-methoxy-phenylphenylphosphine oxyto R(10) Methyl phenyl-β-naphthylphosphine oxyto R(+) Implementation Oxoazaphospholidine [F] prepared according to Example 1
, all phosphinamides of Examples 3-7, Example 9
methylbenzylphenylphosphinate, and especially their optically active isomers.

Example 10 N-methyl-N-(1-mef-2-iodo-2-phenyl)-ethyl (Is, 28
) Production of fosponamide R.

This compound was obtained by reacting oxoazabosporidine (1) of Example 1 with methyl iodide.

30.11! In a flask, 0.1 mol of oxoazaphospholidine [F] was dissolved in 500 mJ of toluene, and then 0.5 mol of methyl iodide was added with stirring. The mixture was heated in so'c for 1 hour under nitrogen atmosphere. Upon standing, a clear yellow oil separated.

Toluene and excess methyl iodide were evaporated.

The oil obtained by evaporation of toluene was chromatographed on basic alumina with ethyl acetate as eluent. The phosphine amide was recovered after 10 distillations of the 150 mA' eluent. The pure product is crystalline and its RMN properties are the same as the product of Example 3. However, the yield of crystalline product was only about 7% compared to 60% for the product of Example 3 prepared without solvent.

This example shows that prolonged heating at 80° C. in the presence of light results in low yields of phosphinamide. If the reaction is carried out in the dark under a nitrogen atmosphere with the exclusion of humidity for only 12 minutes, the yield is over 60%.

Example 11 Preparation of P-methyl-P-phenyl-N-methyl-N-(1-methyl-2-bromo-2-phenyl)ethylphosphineamide.

This method for producing phosphinamide differs from the method for producing phosphinamide in Example 3 in that methyl bromide is gaseous and cannot be easily reacted with solid oxoazaphospholidine.

The following operating pattern was used.

Gaseous methyl bromide was blown in excess into 500 ml of the toluene solution of oxoazaphospholidine [F] of Example 1 at 80° C. for A hours. All solvent and excess methyl bromide were then removed. The oil obtained by evaporation of toluene was chromatographed on alumina using ethyl acetate as eluent.

The yield of the reaction was less than 5%, confirming the conclusion of Example 10. The phosphinamide was recovered after 100 ml of solvent had been distilled off 10 times. It is oily and NMR
The test results are as follows.

Double line (3H) 1.1 (ppm) Double line (3
H) 1.9 Double line (3H) 2.4 Multiple # (IH) 4.5 Double line (IH) 5 Double line (IOH) 7.2-8 This compound is a new compound.

Example 12 (-)3,4-dimethyl-2,5-diphenyl-1,3
, 2-okinoazaphosphoridi(28,4R,5S), ie, the preparation of the enantiomer compound of compound [F] described in Example 1.

Therefore, the procedure of Example 1 was repeated exactly starting from (+)ephedrine instead of (-)ephedrine. The obtained compound had very good chemical and diastereomeric purity.

The melting point is 100°C (recrystallized from toluene), and the NMR characteristics are the same as those of compound [F] shown in Example 1, while its [α]29° is -40°±5 (C
= 2.5 CeHa). In addition, the compound [F
] was +40°±5.

Here, the novel (-)oxoazaphospholidine has the following configuration.

Example 13 (+)N-methyl-N-(1-methyl-2-iodo-2
-Phenyl)ethyl (15,2S)P-methyl-P-phenylphosphineamide (2) in a solvent without heating.

The starting compounds are the same as in Example 3.

However, the starting compound was dissolved in an equal mixture of benzene and cyclohexane. That is, 0.01 mol of oxoazaphospholidine (F in Example 1) was added to 250 ml
was dissolved in 80 WLl of the above mixed solvent in a flask having a volume of . To this, 0,035 mA which had been previously filtered over basic alumina! of CH3I was added. The inside of the flask was cleaned with a stream of nitrogen, sealed under this inert atmosphere, and left in the dark at room temperature for 72 hours. After some time, a partially crystallized oil was deposited at the bottom of the flask. The solvent was then evaporated and the product was subjected to NMR analysis.
The phosphinamide yield was 84%.

Recrystallization from acetone gave a pure product, identical to Example 3 (Q).

From the comparison with Examples 10 and 11, it is clear that a significant improvement is made due to the reaction at room temperature in the dark and protected from moisture.

Example 14 (-)N-methyl-N-(1-methyl-2-iodo-2
-phenyl)ethyl (IR, 2R) P -,! -1
-Production of p-phenylphosphineamide (S).

This compound was designated as (G) in Example 3.
It is the enantiomer of phosphinamide.

This compound is prepared from the (-)oxoazaphospholidine of Example 12, which starts from (+)ephedrine.

Now, the above phosphine amide (S) is produced by a method similar to that disclosed in Example 13 in a similar mixed solvent of an aromatic hydrocarbon and an alicyclic hydrocarbon.

It has a similar yield and similar properties to compound C). However, the rotational force [α] -1 is not +162.5° but -
162.5° (C=2.5 CH30H).

Example 15 (+)N-methyl-N(1-methyl-2-)romu2
-Phenyl)ethyl (Is, 28) Preparation of P-benzyl-P-phenylphosphineamide (2).

This is the same compound as in Example 5. However, the raw materials were previously dissolved in a 1=1 mixture of benzene/cyclohexane, and the reaction was carried out in a homogeneous medium under cooling. 0.01 mol of oxoazaphospholidine [F] and 0.03 mol of purified CH,Br were used as a solution in a solvent mixture of 807J. Leave at room temperature for 7 days, shielding from nitrogen atmosphere, light and moisture, and leave for 3 days.
．． Crystals of 52 diastereomers were collected.

The yield of phosphinamide (2) was 60.3% based on the starting material oxoazaphospholidine.

Example 16 Application of the phosphinamide C) of Example 3 to the preparation of the corresponding methylphosphinate.

The process is similar to the phosphinate preparation of Example 7, except that the reaction medium is brought into contact with an ion exchange resin as a catalyst.

0,413 f (0
,001 mol) of phosphine amide was added to 17 of the acidic ion exchange resin POWEX 50W. Ion exchange resin is 10% HC1 in advance! Wash with an aqueous solution, then with water,
It was further washed with methanol and dried. 1 at room temperature
After stirring for an hour, the mixture was filtered and the methanol was evaporated.

The resulting residue was chromatographed on silica using acetone as eluent.

The product is [α piece −147°(c −=2 Ca H6
) and methylphosphinate with an optical purity of 82%.

The ion exchange resin used as the new catalyst has the advantage that it can be easily separated by filtration alone.

Example 17 The phosphinamide ① obtained according to Example 13 was converted to methylphosphinate in the same manner as in Example 16.

Instead of a phosphinate with configuration R(+) as in Examples 7 and 13, configuration 5(-) was used.

This compound had an angle of 45° (C22CeHa) and an optical purity of 78%.

Agent: Patent Attorney Nobuo Kogawa - Patent attorney Kenteru Noguchi Patent Attorney Kazuhiko Sai

Claims (1)

[Claims] 1. A novel phosphine amide compound represented by the following general formula. However, in the formula, R1, R3 and R6 are groups selected from the group consisting of Ca"Ca alkyl group, phenyl group, substituted phenyl group, and benzyl group, R4 and R5 are hydrogen atoms, and !7, R ” and R7 are CI to C4 alkyl groups, and X is a halogen atom. Oxoazaphospholidine represented by the general formula 2 and an organic halide represented by the general formula
) A method for producing a novel bosphinamide compound represented by the general formula (Q) by conducting the reaction in a dark place while blocking air and moisture.R?R1, where R1 and R3-R7 are hydrogen atoms, or are the same or different aliphatic, alicyclic, and/or aryl hydrocarbon groups, X is a chlorine, bromine or iodine atom, and R2 is alkyl, arylalkyl, aryl,
Cycloalkyl is still saturated silver with ester, ether or ketone functionality.