JP2002069086A - Optically active phosphorus compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an optically active phosphorus compound available as a ligand of a catalyst for asymmetric synthesis. SOLUTION: This optically active phosphorus compound has the general formula (I) (R1, R2, and R3 are each a hydrocarbon residue which may has a substituent, and R2 and R3 may be bonded together to form a ring).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The invention of this application relates to a novel optically active phosphorus compound. More specifically, the invention of this application relates to an optically active phosphorus compound used as a ligand of an asymmetric reaction catalyst.

[0002]

2. Description of the Related Art In recent years, it has been clarified that many biological substances are optically active substances, and it is possible to elucidate the action of substances in the body, develop drugs and agricultural chemicals, and manufacture dyes. In various fields such as biology, medicine, pharmacy, and agriculture, establishment of a method for synthesizing an optically active substance has become an important issue.

[0003] Optically active substances have optical isomers. Therefore, in order to obtain only one kind of optical isomer, it is necessary to synthesize one of the optical isomers by some method or to separate the optical isomers. Asymmetric synthesis, which is one of such methods, involves synthesizing one of the optical isomers by asymmetric induction, and is indispensable as a method for synthesizing an optically active substance. So far, various reaction systems and catalyst systems have been studied and reported.

[0004] Asymmetric induction is based on a chiral center in the same molecule, or with a reagent or catalyst having an asymmetric structure.
Further, the operation may be performed under asymmetric physical conditions such as circularly polarized light. Among them, catalysts having an asymmetric structure are:
In particular, since the three-dimensional structure, electrical properties, and the like can be changed depending on the target compound to design a compound having optimal conditions, it has been widely studied, and various compounds have been synthesized.

[0005] Among such asymmetric reaction catalysts, a transition metal complex having a transition metal capable of taking various charges as a central metal is not only excellent as a catalyst, but also has a catalytic activity of a central metal or a metal. It is of particular interest that it changes significantly by changing the ligand and is relatively easy to design. In metal complex catalysts, since the charge and charge transfer of the central metal vary greatly depending on the ligand to be bound, it can be said that selection of the ligand is important in designing and synthesizing the asymmetric synthesis catalyst.

On the other hand, as reagents having an asymmetric structure that causes asymmetric induction, compounds having chirality in phosphorus such as chiral phosphine (PH ₃ ) compounds and phosphonate (PHO ₃ ^2- ) compounds are known. . These optically active phosphorus compounds have been reported as reagents that can produce products having different absolute configurations by changing their substituents, and various asymmetric compounds using such optically active phosphorus compounds as reagents have been reported. Synthetic reactions are being studied.

Further, those coordinating to a metal in such an optically active phosphorus compound are important as ligands in considering a transition metal complex catalyst.

[0008] As the new optically active phosphorus ligand, for example, those having two phosphorus coordination sites which are completely sterically and electrically different from each other are ones which give the transition metal complex catalyst a unique property. Be expected.

Accordingly, the invention of this application has been made in view of the above circumstances, and has as its object to provide an optically active phosphorus compound which is effective as a ligand of an asymmetric synthesis catalyst.

[0010]

Means for Solving the Problems The invention of the present application is to solve the above-mentioned problems, and firstly, the chemical formula (I)

[0011]

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(However, R ¹ , R ² , and R ³ each represent a hydrocarbon group which may have a substituent, and R ² and R ³ may combine to form a ring.) The optically active phosphorus compounds shown are provided.

Second, the invention of this application is based on the chemical formula (I
I)

[0014]

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(Where Ph represents a phenyl group which may have a substituent).

Third, the invention of this application relates to a method for producing the optically active phosphorus compound, which comprises adding diphenylphosphine to a compound represented by the following formula (III) in the presence of a base:

[0017]

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(Where Ph represents a phenyl group which may have a substituent), and further reacted with borane-THF to obtain a chemical formula (IV)

[0019]

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(Where Ph represents a phenyl group which may have a substituent) The present invention provides a method for producing an optically active phosphorus compound, wherein the compound is deboraneated.

Fourth, the invention of the present application provides a method for producing an optically active phosphorus compound as described above, wherein the compound represented by the chemical formula (III) is represented by the following chemical formula (V)

[0022]

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(Where Ph represents a phenyl group which may have a substituent)
A method for producing the above optically active phosphorus compound obtained by reacting with methanesulfonyl chloride in the presence of P and a base is provided.

Fifthly, the invention of this application is based on the fact that the alcohol of the above formula (V) is replaced by the following formula (VI)

[0025]

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(Where Ph represents a phenyl group which may have a substituent). Also provided is a method for producing the above optically active phosphorus compound obtained by reducing the carboxylic acid represented by the formula:

Further, the invention of this application is based on the sixth aspect that the carboxylic acid of the above formula (VI) is reacted with 1,4-dihalogenobutane and a metal and then with phenylphosphine and borane-THF. The following chemical formula (VII) obtained

[0028]

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(Where Ph represents a phenyl group which may have a substituent) A method for producing the above optically active phosphorus compound obtained by separating a carboxylic acid isomer obtained by carboxylating the compound. I will provide a.

Seventh, the invention of this application relates to an optically active phosphorus ligand which is the optically active phosphorus compound of the first or second invention, and eighthly, the optically active phosphorus coordination. The present invention also provides a metal complex having an atom, and ninthly, an asymmetric reaction catalyst comprising the metal complex.

[0031]

BEST MODE FOR CARRYING OUT THE INVENTION The optically active phosphorus compound of the invention of the present application is a 5-membered ring containing a phosphorus atom in the ring (phosphorane: ph
In Ospholane), an electrical property, and R ¹ attached to the phosphorus phosphorane as two phosphorus coordination centers with different steric properties, the compound having a phosphorus substituent R ^2, R ³ are bonded, respectively.

[0032]

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In this optically active phosphorus compound, R ¹ , R ² and R ³ are hydrocarbon groups which may have a substituent, and R ² and R ³ are bonded to form a ring. It may be. These hydrocarbon groups of R ¹ , R ² and R ³ may be the same or different, but by selecting them, the electrical properties and steric properties of each phosphorus coordination center can be determined. Can be controlled. Examples of R ¹ , R ² , and R ³ include, for example, an alkyl group, a vinyl group, an allyl group, and an aryl group which may have a substituent, and preferably have a substituent. And a phenyl group which may have a substituent.

[0034]

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In this compound, phenylphosphine and diphenylphosphine become two phosphorus coordination centers having different electric and steric properties.

In the optically active phosphorus compound of the invention of this application, phenylphosphine and diphenylphosphine in the chemical formula (II) may have a substituent on each phenyl group. For example, halogen, O,
It may have a substituent containing an atom such as N or S,
It may be a benzyl group, a styryl group or the like. By bonding these substituents, it becomes possible to control the electrical properties and steric properties of each phosphorus coordination center.

The optically active phosphorus compound of the invention of this application is
In addition, it effectively acts as a ligand of a metal complex. The invention of this application also provides a metal complex having such a ligand, and such a metal complex includes those which suitably act as an asymmetric reaction catalyst.

Therefore, as described above, the asymmetric reaction catalyst of the invention of this application can be prepared by selecting R ¹ , R ² , R ³ and its substituents in the optically active phosphorus compound as a ligand. It is also possible to control the properties.

Various methods can be considered for producing the optically active phosphorus ligand of the invention of this application. For example, the following chemical formula (III)

[0040]

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(Where Ph represents a phenyl group which may have a substituent), and further reacted with borane-THF to obtain a chemical formula (IV)

[0042]

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The compound (II) can be obtained by removing the compound of the formula (where Ph represents a phenyl group which may have a substituent).

At this time, the reaction conditions and the method for producing the compound (III) as a raw material are not particularly limited. Compound (II
As a production method of I), for example, the following chemical formula (V)

[0045]

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(Where Ph represents a phenyl group which may have a substituent),
Methods for reacting with methanesulfonyl chloride in the presence of P and a base are contemplated. Of course, conditions such as the reaction solvent, temperature, and time are not particularly limited.

The alcohol of the compound (V) may be obtained by any method.
The following chemical formula (VI)

[0048]

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(Where Ph represents a phenyl group which may have a substituent). As the reduction method, any method such as a method of reduction with a borane-solvent system, a method of reduction after methyl esterification and the like may be used.

Further, the carboxylic acid of the above formula (VI) can be obtained by various methods. For example, a commercially available 1,4-dihalogenobutane is used as a starting material, and after reacting with a metal such as lithium or magnesium, phenyl is added. Reaction with phosphine and borane-THF gives the following chemical formula (VII)

[0051]

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(Where Ph represents a phenyl group which may have a substituent) 1-phenylphosphorane 1-
Borane can be used, and a carboxylic acid obtained by carboxylating the borane can be used. At this time, since optical isomers are generated, it is preferable to separate them, but they may be separated in a later step.

The optically active phosphorus compound of the invention of this application is
It is not limited to the one manufactured by the method described above, and may be manufactured by any method or procedure.

Hereinafter, examples will be shown, and embodiments of the present invention will be described in more detail. Of course, the present invention is not limited to the following examples, and it goes without saying that various aspects are possible in detail.

[0055]

EXAMPLES In the following Reference Examples and Examples, ¹ H,
^{The 13} C and ³¹ P NMR spectra were 300 MHz
Alternatively, it was measured using a 400 MHz NMR spectrometer manufactured by JEOL. ^{For 1} H and ¹³ C, deuterated solvents were used. The chemical shift in ³¹ P NMR is
It was asked to PPh ₃ external standard as a reference.

The IR spectrum was measured by placing a compound as a thin film on a KBr cell.

The melting point was used without correcting the value recorded on the hot stage apparatus.

The solvents used were all purified according to the usual procedures for chemical experiments, and the reagents were used as received without purification.

The reaction was carried out according to the following synthesis scheme (A).

[0060]

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Reference Example 1 1-phenylphosphorane 1
Synthesis of borane (compound 1) In a 500 ml three-necked flask containing a solution of Mg dust (24.3 g, 1.00 mol) in ether (400 ml) at 0 ° C. under an Ar atmosphere, 1,4-dibromobutane (48.0 ml, 400 mmol) in ether (100 ml) was added dropwise. When the addition was completed, the resulting gray solution was stirred at room temperature for 3 hours.

This di-Grignard reagent was added to a dropping funnel connected to a 1-liter three-necked flask containing a solution of phenylphosphine (54.0 ml, 400 mmol) in ether (100 ml).
It was introduced through a tube and added dropwise at 0 ° C. over about 2 hours under Ar. After stirring the resulting suspension under Ar for 24 hours,
To this reaction solution, borane-THF (400 ml, 400 mmol) was added dropwise over about 1 hour, and the resulting suspension was further stirred for 1 hour.

The reaction was quenched with 1N aqueous HCl and extracted with ethyl acetate.

The obtained organic phase was washed with brine and extracted with Na ₂
After drying over SO ₄ , it was filtered and the filtrate was concentrated under reduced pressure.

The residue with an unpleasant odor was chromatographed (SiO ₂ -E7734; EtOAc / hexane = 15).
/ 85) to give a colorless and odorless viscous oil (2
2.0 g, 31%).

The results of product identification are shown in Table 1.

[0067]

[Table 1]

Reference Example 2 (1R ^* , 2S ^* )-and
(1R ^* , 2R ^* )-1-phenylphosphoryl 1-bora
Synthesis of 2-carboxylic acid (compounds 3 and 2) (-)-sparteine (7.1 ml, 31 mmol) or TMED
To a solution of A in ether (50 ml) was added n-BuLi (31.0 ml,
30.9 mmol) was added dropwise at -78 ° C under Ar.

The temperature of this mixture was raised to 0 ° C.
After stirring for 1 minute, compound 1 (4.85
g, 25.7 mmol) in ether (50 ml).

After the obtained yellow solution was further stirred at -78 ° C. for 3 hours, a piece of dry ice was further added. The mixture was allowed to warm to room temperature overnight while stirring at -78 ° C.

The reaction was quenched with 1N aqueous HCl at 0 ° C. and extracted with ethyl acetate. The organic phase is Na ₂ SO ₄
After drying over and filtering, the filtrate was concentrated in vacuo.

The residue was chromatographed (SiO ₂ -E
7734; gradient elution: EtOAc / hexane = 50/5
0-80 / 20) to give a white solid (86% -92).
%).

This solid was washed with ether / hexane (1/2)
After dissolving in a mixed solvent and slowly evaporating the solvent at room temperature, a colorless crystalline solid (17-33%) was obtained. This was found to be (1R ^* , 2S ^* )-1-phenylphosphoryl 1-borane-2-carboxylic acid (compound 3) by X-ray crystallography.

The solution before recrystallization includes (1R ^* , 2S ^* )-
And (1R ^* , 2R ^* )-1-phenylphosphoryl 1
Both -borane-2-carboxylic acid (compounds 3 and 2) were mixed.

Table 2 shows the identification results of compound 3.

[0076]

[Table 2]

Reference Example 3 (1R ^* , 2S ^* )-1-F
Phenylphosphoryl 1-borane-2-carboxylic acid (compound
Object 3) of the separation Compound 3 (6.50 g, 29.3 mmol) and quinine (9.49g, 29.3mm
ol) in CHCl ₃ (150 ml) was stirred at room temperature for 30 minutes, then Et ₂ O (150 ml) was added to promote crystallization of compound 3.

The resulting white precipitate was collected by filtration,
HCl ₂ (100 ml) and Et ₂ O (100 ml) were added for crystallization. This procedure was repeated twice.

The resulting ammonium salt (2.95 g, 18%) was collected by filtration and dried under high vacuum.

The optical purity of the separated compound 3 was determined by HPLC using a chiral column as the corresponding methyl ester or the methyl ester obtained by reduction (compound 3 ′) or alcohol (compound 4). <Reference Example 4> (1R, 2S) -methyl 1-phenyl
Phosphoryl 1-borane-2-carboxylate (compound
Preparation of compound 3 ′) Compound 3 (11.1 mg,
50 μmol). Dissolve in methanol (0.5ml) and add TM
SCH ₂ N ₂ (180 μl, 7.3 equiv.) Was added dropwise to give a yellow solution. To this solution, add a few drops of 10% acetic acid aqueous solution,
TMSCH ₂ N ₂ was quenched. In the same manner, a racemate was synthesized, and HPLC (Chiralpak AD; 2-propanol /
Hexane = 1/120; flow rate: 1.0 ml / min; R _T : 33 mi
n, 41 min).

Table 3 shows the results of identification of the obtained compound 3 '.

[0082]

[Table 3]

<Reference Example 5>(1R, 2S) of compound 3
-1-phenylphosphoryl 1-borane-2-methano
(Compound 4) To a THF solution of the obtained compound 3 (58.5 mg, 264 μmol)
BH at 0 ° C. under Ar _ThreeDMS (95 μl, 3.7 equiv.)
Was added. The resulting mixture was stirred at room temperature for 5 hours and 1N
After quenching the reaction with aqueous HCl, extract with EtOAc.
Issued.

The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum.

The residue was chromatographed (SiO ₂ -E
7734; EtOAc / hexane, 40/60) to give a colorless oil, which after a while
Solidified to a white solid (45.8 mg, 78%).

The racemate is obtained in a similar manner,
(Chiralcel OD; 2-propanol / hexane = 1 /
30; flow rate: 1.0 ml / min; R _T : 22 min, 33 min).

Table 4 shows the results of identification of the obtained compound 4.

[0088]

[Table 4]

Reference Example 6 (1R ^* , 2S ^* )-and
(1R ^* , 2R ^* )-(-)-menthyl 1-phenylphos
Holyl 1-borane-2-carboxylate (Compound 1
2/14, 11/13) (absolute configuration of optically active substance)
Confirmation) In order to confirm the absolute configuration of the optically active substance, compounds 12/14 and 11/13 were produced according to the following chemical formula (B).

[0090]

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Compound 3 (22.2 mg, 100 μmol)
1) In a mixed solution of an alcohol (15.6 mg, 100 μmol) solution and DMAP (0.6 mg) in CH ₂ Cl ₂ (1 ml), DCC (22.7 mg, 110 μmo) was added.
l) was added at 0 ° C. and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was diluted with CH ₂ Cl ₂ (5 ml), washed with water, dried over Na ₂ SO ₄ , filtered,
The filtrate was concentrated under vacuum.

The obtained residue was subjected to column chromatography.
(SiO_Two-E7734; CH_TwoCl _Two/ Hexane = 50
/ 50), two white solids were obtained.
Was.

The less polar solid (10.1 mg, 2
8%) is the inseparable (1R ^* , 2R ^* )-acid (-)
-Diastereomer mixture of methyl ester (compound 1
1/13) (partial racemization occurred during the coupling reaction) and the more polar solid (16.7 mg,
46%) was a diastereomer mixture of the inseparable (-)-methyl ester of (1R ^* , 2S ^* )-acid (compound 12/14).

When the compound having a higher polarity was recrystallized in Et ₂ O / hexane (1/1), (1S, 2R)
The (-)-methyl ester of the acid (compound 14) was obtained as colorless crystals. Furthermore, the (-) of (1S, 2S) acid
-Methyl ester (Compound 13) was similarly obtained from the less polar compound, and X-ray crystallography revealed the absolute configuration of the two compounds.

Tables 5 and 6 show the identification results of compounds 13 and 14, respectively.

[0096]

[Table 5]

[0097]

[Table 6]

Reference Example 7 The compound (1S,
2R) -1-phenylphosphoryl 1-borane-2-me
Synthesis of Tanol (Compound 4) Compound 14 (13.3 g, 36.9 μmol) was converted to CH under Ar
Dissolved in ₂ Cl ₂ (0.5 ml). The solution was cooled to −78 ° C. and DIBAL-H / hexane (100 μl, 100 μm
l) was added dropwise, and the mixture was stirred at -78 ° C for 1 hour.
And quenched with 0.5N aqueous sodium potassium tartrate solution.

Normal washing operation and column chromatography (SiO ₂ -E7734; EtOAc / hexane = 4)
5/55), a colorless oil (6.0 m) was obtained.
g, 78%).

The optical purity was determined by HPLC as described above.
( _RT : 33 min, 100% ee).

The same alcohol (compound 4) was obtained by reduction of compound 3 ′ (105 mg, 444 μmol) (70.7 mg, 77%). <Reference Example 8> (1R, 2S) -1-phenyl phosphoryl
1-borane-2-methyl-methanesulfonic acid (compound
Compound 5) A solution of compound 4 (383 mg, 1.84 mmol) in methanesulfonyl chloride (285 μl, 3.68 mmol) and DMAP (22 mg) in C
To a mixed solution of H ₂ Cl ₂ (15 ml) solution was added Et ₃ N (520 μl,
3.73 mmol) was added. After stirring at room temperature for 12 hours, the mixture is concentrated under vacuum and the residue is subjected to column chromatography (SiO ₂ -E7734; EtOAc / hexane = 40).
/ 60) to give a white solid (526 mg, 100%)
I got

The results of identification of Compound 5 are shown in Table 7.

[0103]

[Table 7]

Reference Example 9 (1R, 2S) -2-diff
Phenylphosphinomethyl-1-phenylphosphoryl P,
P-diborane (compound 6) n-BuLi (3.30 ml, 5.00 mmol) was converted to diphenylphosphine (870 μl, 5.00 mmol)
Was added dropwise to a THF (15 ml) solution at -78 ° C under Ar. After the entire amount was dropped, the cooling bath was removed, and the red reaction solution was further stirred for 1 hour.

The reaction solution was cooled again to -78 ° C.
Compound 5 (715 mg, 2.50 mmol) cooled to 8 ° C. in THF
(15 ml), added to the solution, stirred at -78 ° C for 1 hour,
The temperature was raised to room temperature again, and the mixture was further stirred for 30 minutes.

The mixture was cooled again to −78 ° C.
THF (5.0 ml, 5.0 mmol) was added dropwise with a syringe. After stirring for 30 minutes, the reaction was quenched with 1N aqueous HCl and extracted with CH ₂ Cl ₂ .

After drying the organic phase over Na ₂ SO ₄ and filtering, the filtrate was concentrated in vacuo. Column chromatography (SiO ₂ -E9385; Et ₂ O / hexane = 20 /
80) to give a colorless oil (0.68 g, 70
%)was gotten.

In the same manner, tosylate (126 mg, 3 mg
Diborane (106 mg,
78%).

Table 8 shows the results of the identification of Compound 6.

[0110]

[Table 8]

Example 1 (1R, 2S) -2-diphenylphosphinomethyl-1-phenylphosphorane (compound 7) A solution of compound 6 (680 mg, 1.74 mmol) in pyrrolidine (75 ml) was heated to 55 ± 5 ° C. Heat and stir for 30 minutes. After cooling (<40 ° C.), the solution was concentrated in vacuo and the residue was purified by column chromatography (SiO ₂ -E9385; Et ₂ O / hexane = 5/95) to give a colorless viscous oil (523 mg, 83 %).

Table 9 shows the results of identification of the compound 7.

[0113]

[Table 9]

[0114]

As described in detail above, the present invention provides an optically active phosphorus compound useful as a ligand for an asymmetric synthesis catalyst. Further, a method for producing the optically active phosphorus compound is provided.

Claims (9)

[Claims] [Claim 1] Chemical formula (I) (However, R ¹ , R ² and R ³ each represent a hydrocarbon group which may have a substituent, and R ² and R ³ may be bonded to each other to form a ring) Active phosphorus compounds. 2. The chemical formula (II): (Where Ph represents a phenyl group which may have a substituent). 3. The method for producing an optically active phosphorus compound according to claim 2, wherein diphenylphosphine and the following chemical formula (III) are present in the presence of a base. (Where Ph represents a phenyl group which may have a substituent), and further reacted with borane-
Chemical formula (IV) obtained by reacting with THF 3. The method for producing an optically active phosphorus compound according to claim 2, wherein the compound (wherein Ph represents a phenyl group which may have a substituent) is deboraneized. 4. The method according to claim 3, wherein the compound of the formula (III) is represented by the following formula (V): (Where Ph represents a phenyl group which may have a substituent), and the alcohol represented by the formula (I) is obtained by reacting with methanesulfonyl chloride in the presence of DMAP and a base. Production method. 5. The production method according to claim 4, wherein the alcohol represented by the chemical formula (V) is converted to a compound represented by the following chemical formula (VI): (Where Ph represents a phenyl group which may have a substituent). The method for producing an optically active phosphorus compound according to claim 4, which is obtained by reducing a carboxylic acid represented by the following formula: 6. The method according to claim 5, wherein the carboxylic acid of the formula (VI) is prepared by reacting 1,4-dihalogenobutane with a metal, and then reacting phenylphosphine and borane.
The following chemical formula (VII) obtained by reacting with THF: 6. The method for producing an optically active phosphorus compound according to claim 5, wherein the compound is obtained by separating a carboxylic acid isomer obtained by carboxylating a compound (where Ph represents a phenyl group which may have a substituent). 7. An optically active phosphorus ligand which is the optically active phosphorus compound according to claim 1 or 2. 8. A metal complex having the optically active phosphorus ligand according to claim 7. 9. An asymmetric reaction catalyst comprising the metal complex of claim 8.