CS201028B2 - Method of producing dialkyl-oxophosphonates - Google Patents

Description

The invention relates to a process for the preparation of novel dialkyl-substituted oxophosphonates which are useful as intermediates for the preparation of prostaglandin analogs, in particular for the preparation of the novel 15-substituted omega-pentanorprostaglandins described in U.S. Pat. No. 201,027.

Accordingly, the invention provides a process for producing dialkyl oxofosfonátů formula IV ^0? X ^0R

Ar- (CH _{2) n} -C-CH ₂ -P

OR (IV) wherein

Ar is alpha-furyl or beta-furyl, alpha-thienyl or beta-thienyl, alpha-naphthyl or beta-naphthyl, 3,4-dimethoxyphenyl or phenyl optionally monosubstituted by phenyl, methyl or methoxy ,

H represents an alkyl group having 1 to 4 carbon atoms and n is an integer having a value of β to 5, wherein when Ar is a phenyl group optionally substituted as described above or a naphthyl group, n is 0 or 1, characterized in that with an alkyl ester of formula VO

II

Ar - (CH ₂ ) _n -C -OR (V) (VI) wherein

Ar, R are as defined above, reacted with a dialkylmethylphosphonate of formula VI (ro) ₂ p-ch ₃ in which:

R is as defined above.

The process according to the invention can be described by the following reaction scheme which illustrates the preparation of a preferred dimethyl substituted oxophosphonate. In this reaction scheme, Ar and n are as defined above.

t

Ar (CH ₂ ) _n -COOCH ₃ + (CH ₃ O) ₂ -P-CH ₃

0

II t

Ar- (CH ₂ ) _n -C-CH ₂ -P (OCH ₃ ) ₂ (I) (II) (III)

In accordance with the above scheme, the corresponding dimethyl ester of formula I is condensed with dimethyl methylphosphonate of formula II to give the desired oxophosphonate of formula III.

The invention is illustrated by the following non-limiting examples.

He did

Dimethyl 2-oxo-3-phenylpropyl phosphonate

A solution of 6.2 g (50 mmol) of dimethyl methylphosphonate in 125 mL of dry tetrahydrofuran was cooled to -78 ° C under an atmosphere of dry nitrogen and added dropwise with stirring at 18 ° C over 18 minutes at no rate to -65 °. C, 21 mL of a 2.37 M solution of n-butyllithium in hexane. The resulting mixture was stirred for an additional 5 minutes at -78 ° C and 7.5 g (50.0 mmol) of methyl phenylacetate was added dropwise over 20 minutes at such a rate that the temperature was kept below -70 ° C. The mixture was allowed to react at -78 ° C for 3.5 hours, then allowed to warm to room temperature, neutralized with 6 mL of acetic acid and evaporated on a rotary evaporator under vacuum on a water pump to a white gelled residue. This gel-like material is taken up in 75 ml of water, the aqueous phase is extracted three times with 100 ml of chloroform each, the combined organic extracts are washed again with 50 ml of water, dried over magnesium sulphate and concentrated in vacuo to give a crude residue. g (29%) of dimethyl 2-oxo-3-phenylpropylphosphonate having a boiling point of 134 to 35 DEG C./0.3 Pa.

The NMR spectrum of the product (deuterochloroform) contains a doublet centered at 3.72 δ (J = 11.5 Hz, 6H) for CH 2 Cl 2 _. 0-P-. doublet centered at δ 3.14 (J = 23 Hz, 2H) C-CH to -P _r ~. singII II 1

0 0 years at 3.88 δ (2H) for -CH ₂ -C- and broad singlat at 7.22 δ (5Η) for C ₆ H ₅ -.

In an analogous manner to the above, dimethyl 2-oxo-3- (α-phenylphenyl) propyl phosphonate can be prepared from appropriately substituted methylphenylacetates. These products are suitable for conversion to the corresponding 16-substituted omega-tetranorprostaglandins as described in U.S. Pat. No. 201,027.

Example 2

Dimethyl-2-oxo-3- (p-methylphenyl) propylphosphonet

A solution of 74.5 g (0.6 mol) of dimethyl methylphosphonate in 700 ml of dry tetrahydrofuran was cooled to -78 ° C under an atmosphere of dry nitrogen and 386 ml of a 1.611 solution of n-butyllithium in hexane was added dropwise with stirring over 18 minutes. velocity so that the temperature never rises above -65 ° C. After further stirring for 5 minutes at -78 ° C, 49.1 (0.3 mol) of methyl p-methylphenyl acetate was added dropwise over 20 minutes at such a rate that the reaction temperature of the mixture was kept below -70 ° C. The mixture is allowed to react at -78 ° C for 3.5 hours, then allowed to warm to room temperature, neutralized with 30 ml of acetic acid and rotary evaporated to a white gel-like residue. The gelled material is taken up in 75 ml of water, the aqueous phase is extracted three times with 100 ml of chloroform each, the combined organic solutions are washed with 50 ml of water, dried over magnesium sulphate and concentrated in vacuo to give a crude residue. 47.7%) of dimethyl 2-oxo-3- (p-methylphenyl) propylphosphonate, b.p. 145-147 ° C.

The NMR spectrum of the product (deuterochloroform) contains a doublet centered at 3.75 δ (J = 11.5 Hz, 6H) for (E H, O) ₂ -P-, a doublet centered at 3.14 δ (J = 23 Hz, 2H) for _-C-CH2 -P-,

II II I

O singlet at 3.8 δ (2H) for -CH2-C-. broad singlet at 7.1 δ (4H) for β-C 2 -H. and singlet at

II o

2.3 δ (3H) for p-CH 2 C 9 H 4.

The IR spectrum of the product (chloroform) contains carbonyl absorption at 5.79 > un.

Example 3

Dimethyl 2-oxo-2-phenylethylphosphonate

A solution of 74.5 g (600 mmol) of dimethyl methylphosphonate in 750 mL of dry tetrahydrofuran was cooled to -78 ° C under an atmosphere of dry nitrogen and 265 mL of a 2.34 M solution of n-butyllithium in hexane was added dropwise with stirring. at such a rate that the temperature of the reaction mixture does not rise above -65 ° C by any means. After further stirring for 5 minutes at -78 ° C, 41 g (300 mmol) of methyl benzoethane was added dropwise with stirring at such a rate that the reaction temperature of the mixture was kept below -70 ° C (10 minutes). After reaction at -78 ° C for 1 h, the reaction was allowed to warm to room temperature, neutralized with 35 mL of acetic acid and evaporated to a white gel residue on a rotary evaporator. The gelled material is taken up in 75 ml of water, the aqueous phase is extracted three times with 300 ml of ether each time, the combined organic extracts are washed with 50 ml of water, dried over magnesium sulphate and concentrated to a crude residue in a water pump vacuum. %) of dimethyl 2-oxo-2-phenylethylphosphonate boiling point 130-135 ° C / 5 Pa.

The NMR spectrum of the product (deuterochloroform) contains a doublet centered at 3.78 δ (J = 11.5 Hz, 6H) for (CH-10O-P-, a doublet centered at 3.63 δ (J = 23 Hz, 2H) ) for -C- £ 2 ₂ -P- and a multiplet at 7.3 to 8.2 δ (5Η) for C 8 H 11 -.

Example 4

Dimethyl-2-oxo-3- (p-methoxyphenyl) propylphosphonate

A solution of 74.5 g (600 mmol) of dimethyl methylphosphonate in 700 ml of dry tetrahydrofuran was cooled to -78 ° C under an atmosphere of dry nitrogen and added dropwise with stirring over 10 minutes.

385 ml of a 1.6 M solution of n-butyl lithium in hexane at a rate such that the temperature of the reaction mixture did not rise above -65 ° C under any circumstances. After further stirring for 5 minutes at -78 ° C, 54 g (300 mmol) of methyl p-methoxyphenylacetate was added dropwise over 20 minutes at such a rate that the reaction temperature of the mixture was kept below -70 ° C. The mixture was allowed to react at -78 ° C for 3.5 hours, then allowed to warm to room temperature, neutralized with 55 mL of acetic acid and evaporated on a rotary evaporator to give a white gel-like residue. The gelled residue is taken up in 75 ml of water, the aqueous phase is extracted three times with 300 ml of chloroform each, the combined organic extracts are washed with 50 ml of water, dried over magnesium sulphate and concentrated to a crude residue in a water pump vacuum. 49.4%) of dimethyl 2-oxo-3- (p-methoxyphenyl) propyl phosphonate boiling at 167-195 ° C / 27-40 Pa.

The NMR spectrum of the product (deutero-chloroform) contains a doublet centered at 3.83 δ (J = 11.5 Hz, 6H) for (CH 3 O 4 -P). C.- singlet at ii oo

3.84 Å (3H) for CH 2 O-C 6 H 6 - and a multiplet at 6.82 to 7.41 δ (4Η) for C 8 H 6 -,

Dimethyl 2-oxo-3- (3,4-dimethoxy) phenylpropyl phosphonate can be prepared as described above.

The above products can be converted to the corresponding 16-substituted omega-tetranor prostaglandins of the E and F series as described in U.S. Pat. No. 201,027.

Example 5

Dimethyl-2-oxo-3- (beta-naphthyl) propylphosphonate

A solution of 74.5 g (0.6 mol) of dimethyl methylphosphonate in 750 ml of dry tetrahydrofuran was cooled to -78 ° C under a dry nitrogen atmosphere and 265 ml of a 2.34 M n-butyllithium solution was added dropwise with stirring over 40 minutes. in hexane at a rate such that the temperature of the reaction mixture did not rise above -65 ° C by any means. After further stirring for 5 minutes at -78 ° C, 60 g (0.3 mol) of methyl 2- (beta-naphthyl) acetate was added dropwise over 10 minutes at such a rate that the temperature of the reaction mixture was kept below -70 ° C. The mixture is allowed to react at -78 ° C for 3.5 hours, then neutralized with 35 ml of acetic acid and evaporated to a white gel residue on a rotary evaporator. The gelled material is taken up in 75 ml of water, the aqueous phase is extracted three times with 200 ml of methylene chloride each time, the combined organic extracts are washed with 50 ml of water, dried over magnesium sulphate and concentrated to a crude residue in a water pump vacuum. -3- (beta-naphthyl) propyl phosphonate boiling at 195-200 ° C / < 13 Pa.

The NMR spectrum of the product (deutero - chloroform) contains a doublet centered at 3.72 δ (J =

11.5 Hz, 6H) for (CH ₃ 0) ₂ -P-, doublet centered at δ 3.09 (J = 22 Hz, 2H) fiHg the -C-P- 1 II where

0 0 singlet at 4.0 δ (2Η) for -CHg-C- and multiplet at 7.18 to 7.92 δ (7H) for C ^ qH2.

O

The above product is a suitable starting material for the preparation of Group E or F 16- (beta-naphthyl) -omega-tetranorprostaglandins as described in U.S. Pat. No. 201,027.

Using methyl 2- (alpha-naphthyl) acetate instead of methyl 2- (beta-naphthyl) acetate as described above, dimethyl 2-oxo- (alpha-naphthyl) propyl phosphonate can be prepared, which is a suitable starting material Group E or F (alpha-naphthyl) -omega-tetranorprostaglandins according to the procedure described in the description of the invention to U.S. Pat. No. 201,027.

Example 6

Dimethyl 2-oxo-3- (2-thienyl) propyl phosphonate

A solution of 37.2 g (0.3 mol) of dimethyl methylphosphonate in 400 ml of dry tetrahydrofuran was cooled to -78 ° C under an atmosphere of dry nitrogen and 195 ml of a 1.6 M solution of n-butyllithium in a dropwise solution was added dropwise over 18 minutes. hexane at a rate such that the temperature of the reaction mixture does not rise above -65 ° C by any means. After further stirring at -78 ° C for five minutes, methyl 2- (2-thienyl) acetate (23.4 g, 0.15 mol) was added dropwise over 20 minutes at such a rate that the temperature of the reaction mixture was kept below -70 ° C. The mixture is allowed to react at -78 ° C for 3.5 hours, then allowed to warm to room temperature, neutralized with 6 ml of acetic acid and evaporated to a white gel residue on a rotary evaporator. The gelled material is taken up in 75 ml of water, the aqueous phase is extracted three times with 100 ml of chloroform each, the combined organic phases are washed with 500 ml of water, dried over magnesium sulphate and concentrated to a crude residue in a water pump vacuum. ethyl 2-oxo-3- (2-thienyl) propylphosphonate boiling at 150-152 [deg.] C./7 mbar.

The NMR spectrum of the product (deuterochloroform) contains a doublet with a center at 3.7 δ (J = 11.0 Hz, 6H) for (GH 4 Q 6 -P-. Singlet at 4.12 δ (2H) for Ar-CH 4). -CO-. Doublet with center

II o at 3.16 δ (J = 22 Hz, 2H) for -C-CH3 and a multiplet at 6.8 to 7.3 δ (3H) for the protons of the thienyl residue.

The corresponding beta-thienyl derivative is prepared in an analogous manner in which the signals at 3.65 δ (J = 11 Hz) and 3.1 δ (J = 24 Hz) are present in the NMR spectrum.

Example 7

Dimethyl 2-oxo-4- (2-thienyl) butylphosphonate

A solution of dimethyl methylphosphonate (11.6 g, 94 mmol) in dry dimethylformamide (130 mL) was cooled to -78 ° C under a dry nitrogen atmosphere. To this phosphonate solution was added dropwise over 18 minutes 43 ml of a 2.26 M solution of n-butyllithium in hexane at such a rate that the reaction temperature of the mixture in no way exceeded -65 ° C. After further stirring at -78 ° C for five minutes, 8.0 g (47 mmol) of methyl 3- (2-thienyl) propionate was added dropwise over 20 minutes at such a rate that the temperature of the reaction mixture was kept below -70 ° C. The mixture was allowed to react at -78 ° C for 3.5 hours, then allowed to warm to room temperature, neutralized with 5 ml of acetic acid and evaporated on a rotary evaporator to give a gel-white, white residue. The gelled material is taken up in 75 ml of water, the aqueous phase is extracted three times with 100 ml of chloroform each, and the combined organic extracts are washed with 50 ml of water, dried over magnesium sulphate, evaporated in a water pump vacuum, and distilled. 9.7 g of dimethyl 2-oxo-4- (2-thienyl) butylphosphonate, b.p. 156 DEG C./0.2 mbar, are obtained.

The NMR spectrum of the product (deuterochloroform) contains a doublet centered at 3.75 δ (J = 11.5 Hz, 6H) for (ΟΗ-, Ο) -Ρ-. triplet centered at 3.11 δ (4H) for -CH.-CH-, doublet

I o

center at 3.14 6 (J = 23 Hz, 2H) for -C-CHg-P- and multiplet at 6.7 to 7.4δ (3H) for protons

Of the thienyl ring.

Analogously, methyl 2-oxo-4- (3-thienyl) butylphosphonate, which is also a suitable starting material for the preparation of 17- (3-thienyl) -omega, can be prepared from methyl 3- (3-thienyl) propionate. Similarly, other starting materials suitable for conversion to 18, 19 or 20α of 20-beta-thienyl-substituted prostaglandins can be prepared from the corresponding esters of the corresponding esters.

Example 8

Dimethyl-2-oxo-4- (2-furyl) butylphosphonate

A solution of 25 g (0.21 mol) of dimethyl methylphosphonate in 300 ml of dry tetrahydrofuran was cooled to -78 ° C under an atmosphere of dry nitrogen, and 80 ml of a 2.67 H solution of n-butyllithium in hexane was added dropwise with stirring. at such a rate that the temperature of the reaction mixture does not in any case exceed -65 ° C. After stirring for 5 minutes at -78 ° C, methyl 3- (2-furyl) phosphonate (16.0 g, 0.104 mol) was added dropwise over 20 minutes at such a rate that the temperature of the reaction mixture was kept below -70 ° C. The mixture was allowed to react at -78 ° C for 3.5 hours, then allowed to warm to room temperature, neutralized with 6 mL of acetic acid and evaporated to a white gel residue on a rotary evaporator. The gelled material is taken up in 75 ml of water, the aqueous phase is extracted three times with 100 ml of chloroform each, the combined organic extracts are washed with 50 ml of water, dried over magnesium sulphate and concentrated to a crude residue in a water pump. Of 2-oxo-4- (2-furyl) butylphosphonate boiling at 148-150 ° C / 2 mm Hg.

The NMR spectrum of the product (deuterochloroform) contains a doublet with a center at 3.73 δ (J = 11.5 Hz, 6H) for (fig-jOJj-P-, a singlet centered at 2.95δ (2H) for -CHg-CH 3) -, doublet

II centered at 3.12 6 (J = 23 Hz, 2H) for -C-CHg-P- and multiplets at 5.96, 6.23 and 7.236

O (1H each) for furan ring protons.

Analogously using methyl 3- (3-furyl) propionate instead of methyl 3- (2-furyl) propionate, dimethyl 2-oxo-4- (3-furyl) butylphosphonate can be obtained as a suitable starting material for the preparation 17- (3-Furyl) -omega-trisnorprostaglandins of E and P series. In a similar manner, dimethyl 2-oxo-2- (beta-furyl) ethylphosphonate boiling at 140 ° C / 27 Pa was prepared. This material is a suitable starting material for the preparation of 15- (beta-furyl) -omega-pentanorprostaglandins series E and F.

In a similar manner, dimethyl 2-oxo-2alpha-thienyl-ethylphosphonate can be prepared as a suitable starting material for the preparation of the 15alpha-thienyl-omega-pentanorprostaglandins of series E and F.

In an analogous manner, dimethyl 2-oxo-3- (alpha-furyl) propyl phosphonate, dimethyl 2-oxo-5- (alpha-furyl) pentyl phosphonate, dimethyl 2-oxo-6- (alpha-) can be prepared from the corresponding starting materials. furyl) hexylphosphonet and dimethyl-2-oxo-7- (alpha-furyl) heptylphosphonet. These are suitable starting materials for the preparation of 16, 18, 19 and 20α-furyl-substituted prostaglandins. In the same manner, beta-furyl derivatives are prepared from the corresponding starting materials.

Other compounds prepared as described above are summarized below. These compounds correspond to the general formula

Ar- (CH _{2) n} -C-CH ₂ -P (PCH-j) ₂

II

II

Ar physical constants o-tolyl β-naphthyl α-naphthyl

2-ethylphenyl p-biphenyl β-naphthyl

mp 155-163 ° C / 7 Pa

mp 195 to 200 ° C / 133 Pa (ch) (ch)

m.p. 56-58 ° C (ch) (ch) Preparation according to Example δ.

NMR ( J Hz) 3.75 (11.5) ^x) , 3.10 (23) ( ^xx) 3.72 (11.5) ^x) , 3.09 (22) ( ^xx) 3.75 (11.5) ^X) , 3.06 (23) ( ^xx) 3.83 (1l) ^x) 3.15 ^XX) 3.79 (11.5) ^x , 3.12 ^XX) 3.80 (11.5) ^x) , 3.79 (23) ( ^xx)

legend: (ch) Purified by column chromatography x) methoxy protons xx) protons of the radical -C-CH ₂ -P-

Claims (1)

A process for preparing dialkyl oxophosphonates of formula IV O 0 OR Ar- (C ^H 2) _n -CC ^H 2 -P 4 (IV) OR in which Ar is alpha-furyl or beta-furyl, alpha-thienyl or beta-thienyl, alpha-naphthyl or beta-naphthyl, 3,4-dimethoxyphenyl or phenyl optionally monosubstituted by phenyl, methyl or methoxy group, R is C 1 -C 4 alkyl and n is an integer of 0 to 5, wherein when Ar is phenyl or optionally substituted phenyl or naphthyl as described above, n is 0 or 1, wherein the alkyl ester of formula (V) Ar ( ^CH2 ) _n -C-OR in which Ar, R are as defined above, reacted with a dialkyl methylphosphonate of formula VI (ro) ₂ p-ch ₃ (V) (VI) wherein: R is as defined above,