Process for Preparing Fluorinated Molecules

Abstract

The present invention relates to a process for preparing α-fluorinated esters from α-hydroxy esters by reaction with a dihalocarbonyl compound (or an equivalent) to give haloformates and further to give fluoroformates, which are then decomposed thermally in the presence of suitable catalysts. The invention further relates to the individual steps of the process and in some cases to novel fluoroformates.

Description

EXAMPLES 1 TO 5

In each case 1.0 g of methyl 2S-[(fluorocarbonyl)oxy]propanoate were converted to methyl 2(R)-fluoropropionate under the conditions recorded in table 1. The temperature listed reports the mean bath temperature of the heating medium. The reactions were performed without distilling out the product. The conversions to the target product are recorded in table 1.

The methyl 2(R)-fluoropropionate product was also characterized by its NMR spectrum:

¹H NMR (400 MHz, CD₃CN): δ=1.51 (dd, 3H, H—C3, J₁=23.9 Hz, J₂=6.8 Hz), 3.73 (s, 3H, ester methyl), 5.06 (dq, 1H, 48.3 Hz, J₂=6.9 Hz).

The enantiomeric excess was determined by gas chromatography on a chiral carrier phase.

TABLE 1
		Cat.	KF			t		Conversion	ee*
No.	Cat.	[eq]	[eq.]	T [° C.]	Conc. [%]	[h]	Sol.	[%]	[%]
1	DMAP	0.1	/	90	20	6	MCB	33	95
2	DMAP	0.1	/	90	/	6	/	48	88
3	DMAP	0.1	/	90	20	6	product	83	95
4	CsF	0.1	/	160	20	6	DMAA	42	96
5	18[C]6	0.05	2	120	20	6	DMAA	63	73

Abbreviations for Table 1:

• ee=Enantiomeric excess
• *=Enantiomeric excess at the end of the reaction time;
• Cat.=Decarboxylation catalyst
• Cat [eq]=Amount of cat. in molar equivalents based on reactant
• T=Reaction temperature (mean temperature of the heating medium)
• Conc.=Concentration of reactant at the start of the reaction
• Sol.=Solvent
• Conversion=Conversion of the reaction based on reactant
• DMAP=N,N-dimethylaminopyridine
• MCB=Monochlorobenzene
• DMAA=Dimethylacetamide
• 18[C]6=Crown ether 18-crown-6

EXAMPLES 6-10

In each case 1.0 g of racemic methyl 2-[(fluorocarbonyl)oxy]propanoate was converted to the racemic methyl 2-fluoropropionate under the conditions recorded in table 2. The temperature listed reports the mean bath temperature of the heating medium. The reactions were performed without distilling out the product. The conversions to the target product are recorded in table 2. The methyl 2(R)-fluoropropionate product was also characterized by its NMR spectrum:

¹H NMR (400 MHz, CD₃CN): δ=1.51 (dd, 3H, H—C3, J₁=23.9 Hz, J₂=6.8 Hz), 3.73 (s, 3H, ester methyl), 5.06 (dq, 1H, 48.3 Hz, J₂=6.9 Hz).

TABLE 2
			KF	T	Conc.	t
No	Cat.	[eq]	[eq.]	[° C.]	[%]	[h]	Sol.	Conversion
6	HBGCl	0.1	/	90	40	6	DMAA	83
7	HBGCl	0.1	/	rfx.	40	6	THF	83
8	Bu4NBr	0.1	/	90	20	6	DMAA	91
9	Bu4NBr	0.1	/	90	20	6	xylene	91
10	Bu4NCl	0.1	/	90	20	6	MCB	83

Abbreviations for Table 2: see Abbreviations for Table 1

Further Abbreviations for Table 2:

• HBGCl=hexabutylguanidinium chloride,
• Bu₄NBr=tetrabutylammonium bromide,
• Bu₄NCl=tetrabutylammonium chloride,
• THF=tetrahydrofuran

EXAMPLE 11

4.7 g of pyridine were initially charged in 10 ml of dichloromethane and admixed at room temperature with 1.9 g of pyridine-HF complex (M=99.11 g/mol). 10 g of methyl 2-[(chlorocarbonyl)oxy]propanoate (ee. 99%) were added dropwise to this mixture and the resulting reaction mixture was stirred at room temperature overnight. Subsequently, the mixture was added to semiconcentrated hydrochloric acid, the organic phase was removed and the aqueous phase was reextracted with dichloromethane. The combined organic phases were dried (Na₂SO₄) and concentrated. This afforded 7.8 g of methyl 2-[(fluorocarbonyl)oxy]propanoate with a content of 89% (yield: 77%, ee: 99%). The analyses of the enantiomeric excess were undertaken by means of chiral GC.

¹H NMR (400 MHz, CD₃CN): δ=1.55 (dd, 3H, H—C3, J₁=7.1 Hz, J₂=1.6 Hz), 3.76 (s, 3H, ester methyl), 5.12 (dq, 1H, J₁=7.6 Hz, J₂=1.1 Hz).

EXAMPLE 12

11.2 g of 2-RS-ethylhexyl 2′S-[(chlorocarbonyl)oxy]propanoate were added dropwise at room temperature to a mixture of 3.7 g of potassium fluoride and 0.56 g of the crown ether 18-crown-6 in 25 g of methylene chloride. After stirring overnight, 9.2 g of 2-RS-ethylhexyl 2′S-[(fluorocarbonyl)oxy]propanoate were obtained with a content of 82% (yield: 72% of theory).

¹³C NMR (151 MHz, CD₃CN): δ=11.2 (CH₃CH₂—), 14.3 (C6), 16.9 (C3′), 23.6 (C5), 24.3, 24.4 (CH₃CH₂—), 29.5 (C4), 30.9 (C3), 39.5 (C2), 68.7 (C1), 76.2 (C2′), 145.5 (COF, J=1.9 Hz), 169.9 (C1′).

Having thus described in detail various embodiments of the present invention, it is to be understood that the invention defined by the above paragraphs is not to be limited to particular details set forth in the above description as many apparent variations thereof are possible without departing from the spirit or scope of the present invention.

Claims

1. A process for preparing compounds of the formula (IV), optionally in optically active form,

2. The process as claimed in claim 1, wherein, in the formula (IV),

3. The process as claimed in claim 1, wherein, in the formula (IV), R1 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C6)-cycloalkyl, (C1-C4)-alkyl-(C3-C6)-cycloalkyl or a radical of the formula —CO2R4, —(CH2)nCO2R4, —COR4, —SOR4 or —SO2R4, where n is an integer from 0 to 12, or phenyl,R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C6)-cycloalkyl, (C1-C4)-alkyl-(C3-C6)-cycloalkyl or a radical of the formula —CO2R4, —(CH2)nCO2R4, —COR4, —SOR4 or —SO2R4, where n is an integer from 0 to 12, or phenyl,R3 is (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C6)-cycloalkyl or (C1-C4)-alkyl-(C3-C6)-cycloalkyl andR4 is (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C6)-cycloalkyl or (C1-C4)-alkyl-(C3-C6)-cycloalkyl.

4. The process as claimed in claim 1, wherein an aromatic or heteroaromatic tertiary amine, a phase transfer catalyst and/or a fluoride source is used for the thermal decarboxylation in stage (c).

5. The process as claimed in claim 1, wherein the decarboxylation in stage (c) is performed at temperatures between 60 and 200° C.

6. The process as claimed in claim 1, wherein the reactions are performed using a chiral, non-racemic reactant, and the decarboxylation in stage (c) is conducted enantioselectively in the presence of a decarboxylation reagent or catalyst from the group of DMAP, KF, CsF, tetraalkylammonium chlorides, tetralkylphosphonium chlorides, hexaalkylguanidinium chlorides, hexaalkylguanidinium fluorides and mixtures of the compounds from the aforementioned group.

7. The process as claimed in claim 1, wherein the solvent in stage (c) is a halogenated aromatic, an N,N-dialkylated amide, sulfolane or an ester.

8. The process as claimed in claim 1, wherein from 0.005 to 6 mol of decarboxylation reagent/catalyst are used in stage (c) per mole of compound of the formula (III).

9. A process for preparing compounds of the formula (IV), optionally in optically active form,

10. A process for preparing compounds of the formula (IV), optionally in optically active form, which comprises reacting a compound of the formula (II)

11. A compound of the formula (III), optionally in optically active form, as defined in claim 9.

12. A compound of the formula (III) as claimed in claim 11, wherein R1 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C6)-cycloalkyl, (C1-C4)-alkyl-(C3-C6)-cycloalkyl or a radical of the formula —CO2R4, —(CH2)nCO2R4, —COR4, —SOR4 or —SO2R4, where n is an integer from 0 to 12, or phenyl,R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C6)-cycloalkyl, (C1-C4)-alkyl-(C3-C6)-cycloalkyl or a radical of the formula —CO2R4, —(CH2)nCO2R4—COR4, —SOR4 or —SO2R4, where n is an integer from 0 to 12, or phenyl,R3 is (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C6)-cycloalkyl or (C1-C4)-alkyl-(C3-C6)-cycloalkyl andR4 is (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C6)-cycloalkyl or (C1-C4)-alkyl-(C3-C6)-cycloalkyl.

13. The compound of claim 12, wherein the compound is chiral and non-racemic.