NOVEL ALDEHYDE COMPOSITION

FIELD OF THE INVENTION

This invention relates to a novel composition comprising a regioisomeric mixture of functionalized aldehydes, which is prepared efficiently by a hydroformylation reaction under conditions selected to favour formation of the desired regioisomer. This composition has utility in the manufacture of bifunctional synthetic intermediates for use in pharmaceutical, agrochemical, fragrance chemical and other fine chemical applications.

BACKGROUND TO THE INVENTION

The aldehydes represented by formulae (1) are versatile, differentially protected amino aldehydes that have utility as bifunctional synthetic intermediates in pharmaceutical, agrochemical, fragrance chemical and other fine chemical applications.

(1 ) where Boc is -C(O)OC(CH ₃ ) ₃ . The linear aldehyde (1) is an important intermediate for the manufacture of biologically active compounds of pharmaceutical interest (see for example, Crawford et. al., US20050209277 Al). However, existing synthetic routes to the aldehyde (1), as depicted in Scheme 1 (Crawford et. al., US20050209277 Al) and Scheme 2 (Xiao et. al., Bioorganic & Medicinal Chemistry 12 (2004) 5147-5160), are disadvantaged by the high cost of starting materials (3) and (4) respectively. Scheme 1

Scheme 2

)

Hydroformylation of an olefin is well known in the art for the production of commodity chemicals such as butyraldehyde (see for example Billig et al, US4668651). The reaction has also been applied increasingly as a method to produce higher value functionalized aldehydes from functionalized olefins but this may lead to two regioisomers. It is desirable to identify hydroformylation catalysts and conditions that produce a high excess of a desired compound or regioisomer. In addition, the means to readily remove the unwanted regioisomer may be a prerequisite for effective utilization of the required regioisomer in downstream chemical processes leading to a final product. When investigating the hydroformylation of a specific heteroatom containing α-olefin for the first time, attainment of these desired features cannot be easily predicted. For example, in the hydroformylation of α-olefins of wherein the functional group is a protected or unprotected amino group, the regioselectivity observed in reported examples shows wide variability, as illustrated in Scheme 4 across a range of allylamine derivatives (5) - (7) (Cuny and Buchwald, Journal of the American Chemical Society (1993), 115(5), 2066-2068; Delogu et al., Journal of Organometallic Chemistry (1984), 268(2), 167-174; Sato et al., Nippon Kagaku Zasshi (1969), 90(6), 579-583).

Scheme 4

SUMMARY OF THE INVENTION Thus, according to a first embodiment this invention is a composition comprising a regioisomeric branched aldehyde (2)

where Boc is -C(O)OC(CH ₃ ) ₃ .

According to a second embodiment the composition further comprises an aldehyde of formula (1)

(1 )

DETAILED DESCRIPTION OF THE INVENTION

This composition may be produced efficiently by hydroformylation of N,N-bis(tert- butoxycarbonyl)allylamine (BBAA, formula (8)), entailing reaction with syngas in the

presence of, as a catalyst, a soluble rhodium complex of a phosphorus-containing ligand. The ratio of aldehydes (1):(2) can be controlled by selection of the ligand. Further control of this ratio, if required, to increase the proportion of either aldehyde (1) or aldehyde (2) can be effected by crystallization of the initially isolated composition.

The molar ratio of aldehyde (l):aldehyde (2) according to one preferred embodiment is from 3:1 to 200:1, preferably 10:1 to 200:1. According to a second preferred embodiment the molar ratio of aldehyde (2):aldehyde (1) is from 3:1 to 200: 1, preferably 10:1 to 200:1. Useful catalysts for the present invention include complexes of transition metals, such as preferably Rhodium, with bidentate ligands, preferably bisphosphite ligands. The molar ratio of the ligand to metal is, preferably, 1:1 to 10:1 and, more preferably, 1.1:1 to 2:1. The hydroformylation reaction is preferably carried out using an organic solvent or solvent blend that dissolves the substrate, BBAA, and the ligand/catalyst. More preferably the reaction solvent is tetrahydrofuran. The reaction temperature is, preferably, from 40 ⁰ C to 100 ⁰ C and, more preferably, from 50 ⁰ C to 80 ⁰ C. The reaction solution preferably is agitated at a speed that ensures adequate mass transfer of hydrogen and carbon monoxide into the liquid phase.

In forming a composition comprising predominantly aldehyde (2), an enantiomerically enriched chiral ligand, for example ligand selected from compounds of formulae (13) to (20) and their opposite enantiomers/diastereomers, is used. Most preferably, Ligand (15), (16) and their diastereomers are used to produce compositions comprising greater than 85% aldehyde (2) based on amount of aldehydes (1) and (2). The pressure of hydrogen gas is, preferably, from 30 psia (206 kPa) to 500 psia (3448 kPa) and, more preferably, from 50 psia (345 kPa) to 300 psia (2068 kPa). The pressure of carbon monoxide is, preferably from 30 psia (206 kPa) to 500 psia (3448 kPa) and, more preferably, from 50 psia (345 kPa) to 300 psia (2068 kPa).

(15) (16)

In forming a composition comprising predominantly aldehyde (1), a bidentate phosphine or phosphite ligand, for example ligand represented by formula (9) is used, wherein R ¹ is tert-butyl, methoxy or 2,4,6-trimethylphenyl; R ² is tert-butyl or trimethylsilyl; A is the structural fragment according to formula I in which R ³ is tert-butyl, methoxy or hydrogen and R ⁴ is tert-butyl, trimethylsilyl or hydrogen; B is the same as A when R3 and R4 are both hydrogen or, when R ³ and R ⁴ are not both hydrogen, a structural fragment

according to formulae II or III, in which R ⁵ through R ⁸ are alkyl, halogen, methoxy or hydrogen.

The resulting composition will preferably comprise at least 70% of aldehyde (1) based on amount of aldehydes (1) and (2). The pressure of the syngas for this reaction may be lower than when aldehyde (2) is the desired product. The pressure of hydrogen gas is, preferably, from 10 psia (69 kPa) to 100 psia (689 kPa) and, more preferably, from 20 psia (138 kPa) to 70 psia (483 kPa). The pressure of carbon monoxide is, preferably, from 10 psia (69 kPa) to 100 psia (689 kPa) and, more preferably, from 20 psia (138 kPa) to 70 psia (483 kPa).

More preferably, a ligand of formula (10), (11) or (12) is used to produce a composition comprising at least 90% of Aldehyde (1).

Ligand 10

Ligand 12

The resulting aldehyde is preferably separated from the catalyst by crystallization. The crystallization can be conveniently carried out by cooling the reaction solution to below -20 ⁰ C. One or two recrystallization can optionally be carried out to enrich the desired aldehyde (1) or (2) in the composition.

EXAMPLES All the examples were done using N,N-(bis-Boc)-allylamine (BBAA) purchased from Astatech or Lacamas Lab.

General Protocol

The following experiments may be carried out in an reaction system set up as follows: The reaction system is installed in a dry box with constant purging of nitrogen. It

has eight stainless steel reactor vessels (RVs) with disposable glass liners. Each RV has a gas volume of 20 ml and a working volume of 1 to 5 ml. The RVs are stirred with PEEK impellers at speed of 250 to 1000 rpm, all controlled by a common motor. Both the temperature (1 to 200 ⁰ C with 1 ⁰ C resolution) and the pressure (up to 500 psi) can be controlled individually for each RV, however, the maximum temperature differential for adjacent RVs is 10 ⁰ C. The actual fluid temperature is < 4 ⁰ C and < 8 ⁰ C than reported by the system, for set points from ambient to 100 ⁰ C and above 100 ⁰ C, respectively. The pressure monitoring accuracy is +/- 2 psi or 2% of displayed, whichever is greater.

The reactors are preferably cleaned and purged with nitrogen. The reactors are charged with a tetrahydrofuran (THF) solution of Rh(acetoacetonate)(CO) ₂ , a selected ligand, BBAA and additional solvent to make up reactor compositions. The reactors are purged with 1:1 (CO:H2) syn gas three times, pressurized to the set pressures and then stirred and heated. The progress of the reactions is monitored automatically by gas up take curves to determine the reaction time for each reactor to reach a certain conversion level. The final results are obtained by GC analysis.

Examples 1-5: Hydroformylation of λf,λf-Bis-Boc allyl amine (12; BBAA) using Aldehyde (1) selective catalysts

Experiments run substantially as set forth above are set out in Table I.

Ligand (10) is

Ligand (11) is

Ligand (12) is Table 1

*TO means turnover means that a rhodium catalyst has completed one cycle of catalysis, i.e. it has turned one olefin molecule over to one aldehyde molecule. Turnover/hour measures the average rate of a catalyst in a given period of time under a certain set of conditions.

Example 6: Hydroformylation of N,N-Bis-Boc allyl amine (12; BBAA) using Aldehyde (1) selective catalysts

A reaction is undertaken substantially according to the above protocol using a catalyst solution (Ligand (10) (0.11Og, 0.140 mmol) and Rh(CO) ₂ acac (0.0252g,

0.0977mmol) in 1Og THF) and BBAA solution (20.Og, 97% pure, 75.76 mmol in 2Og THF) which is prepared under nitrogen and were transferred into the reactor under nitrogen. The reactor is purged three times with 60 psi 1:1 syn gas and then pressurized to 60 psia. The reactor is stirred at -lOOORPM (the impeller radius is about 2 cm) and heated to 70 ⁰ C while maintaining the pressure in the reactor at 60 psia. The progress of the reaction is monitored by syngas consumption and is stopped when the amount of syngas consumption reaches

100% conversion of BBAA, which occurs in about 70 minutes. GC analysis of a sample taken from the reactor confirms that the conversion is >99%.

Example 7: Catalyst separation and Aldehyde (1) purification

The hydroformylation reaction solution is collected and cooled to -50 ⁰ C, causing formation of slurry, which is filtered and the solid dried in air to obtain 11.5g partially melted product. The filtrate is concentrated down to about 20 ml and cooled again to -40 ⁰ C to obtain 5.0g crystalline product. Yield for a reaction substantially as in Examples 6 and separated and purified as above was 16.5g, 75.6%. The two batches of product, which were slightly yellow, are combined and dissolved in THF (~65wt% BBAB and ~35wt% THF) and recrystalized at ~ -40 ⁰ C. The crystalline product is filtered quickly, washed with cold (>-40 ⁰ C) pentane and dried under vacuum. Product made substantially as above was 10.5g white crystalline product. ¹ H NMR (CDCl ₃ , 300 MHz, δ): 1.508 (s, 18H), 1.885 (quintet, J=7.5 Hz, 2H's on C3), 2.451 (t of d, J=7.5 and 1.8 Hz, 2H's on C2), 3.600 (t, J=7.5 Hz, 2H's on C4) and 9.759 (t, J=1.8 Hz, IH on Cl). Also found 0.62 mol% of aldehyde (2) with proton on Cl and the methyl at 9.626 (d, J=2.4) and 1.092 (d, J=6.9 Hz) and 0.59 wt% THF

Examples 8 through 20: Hydroformylation of N,N-Bis-Boc allyl amine (8; BBAA) using Aldehyde (2) selective catalysts

Following substantially the general protocol set forth above the following reactions were run with the Ligands (13), (14), (16) and (20). The results are found in Table II Solutions from Exp #8 through 17 were combined for isolation of a composition with >85% Aldehyde (2).

Table II

EXP # 8 9 10 11 12 13 14 15 16 17 18 19 20

Ligand (16) (16) (16) (16) (16) (16) (16) (16) (16) (16) (13) (14) (20)

Temp, ⁰ C 60 60 60 60 60 60 70 70 80 80 60 60 60

Pres, psig ¹ 200 200 400 400 400 400 400 400 400 400 150 150 400

[Rh], ppm 200 200 200 200 200 200 200 200 200 200 200 200 200

Ligand/Rh 1.30 1.30 1.30 1.30 1.30 1.30 1.30 1.30 1.30 1.30 1.30 1.30 1.30

BBAA, M 1.34 1.34 1.34 1.34 1.34 1.34 1.34 1.34 1.34 1.34 1.34 1.34 1.34

Conv, % 100.0 100.0 99.9 99.8 100.0 99.9 99.8 99.8 99.8 100.0 99.2 99.8 9.7

Time, hr ² 2.5 1.75 2.5 2.5 2.5 2.5 0.5 0.5 0.25 0.25 3.0 2.5 3.0

Aldehyde

10.80 11.10 11.32 10.83 10.4 10.3 11.14 11.45 11.29 11.24 32.8 36.1 14.3

(1), mol% ³

Aldehyde

89.20 88.90 88.54 88.96 89.6 89.6 88.51 88.19 88.32 88.76 66.5 63.6 85.5

(2), Mol% ³

Notes for Table 1 :

1. Total pressure of 1 : 1 syn gas.

2. Reaction times were determined by syn gas uptake curves.

3. Mol% of total aldehydes produced.

Example 21: Catalyst separation and Aldehyde (2) purification

A combined reaction solution as stated above is passed through a short (2 inches) silica gel column (1.5 inch in diameter) and washed with about 50 ml THF/pentane (1:4 ratio). The collected clear solution is evaporated to obtain about 12.8g clear colorless oil, which is dissolved in 5 ml toluene. The toluene solution was cooled with dry ice and then placed in a -20 ⁰ C freezer to obtain crystalline solid. The supernatant is decanted, solid washed three times with cold (-20 ⁰ C) pentane, and then placed under vacuum to remove residual solvents. The solid melts when temperature rose to ambient. GC analysis shows an Aldehyde (2)/Aldehyde (1) ratio of 33:1. This oil is dissolved in 0.5 ml toluene and the solution is cooled again with dry ice and then placed in the -20 ⁰ C freezer to obtain crystalline solid. The solid is filtered and washed with cold pentane three times. Most of the solid is dissolved. The remaining solid is transferred into a vial and placed under vacuum to remove residual solvents to obtain about 20 mg clear colorless oil. GC analysis shows an Aldehyde (2)/Aldehyde (1) ratio of 99:1. ¹ H NMR (CDCl ₃ , 300 MHz, δ): 1.070 (d, J=6.9 Hz, 3H, methyl); 1.427 (s, 18H, t-butyl groups), 2.663 (complex, lH's on C2), 3.661 (d of d, J=14.0 and 5.4 Hz, lH's on C3), 3.905 (d of d, J=14.0 and 8.1 Hz, lH's on C3) and 9.608 (d, J=2.4 Hz, IH on Cl). Also found 0.67 mol% of Aldehyde (1) with proton on Cl at 9.747 (U=I.8).

CONCLUSION

While the instant invention has been described above according to its preferred embodiments, it can be modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the instant invention using the general principles disclosed herein. Further, the instant application is intended to cover such departures from the present disclosure as come within the known or customary practice in the art to which this invention pertains and which fall within the limits of the following claims.