CN1706802A - Prepn process of 2-ary lactate, naprosyn and ibuprofen - Google Patents

Abstract

The present invention provides convenient and cheap process of synthesizing 2-aryl lactate and its derivatives. Under the action of Lewis acid and in the condition with or without alkali, the rich-electron place of arene and acetonate produce Friedel-Crafts reaction directly to prepare 2-aryl lactate in high yield. The said process has mild condition and easy-to-obtain material and is suitable for industrial production. The product may be further dewatered, reduced and saponified to prepare the derivatives naprosyn, ibuprofen, etc.

Description

A kind of method for preparing 2-ary lactate and Naproxen Base, Ibuprofen BP/EP

Technical field:

The present invention relates to a kind of preparation method of 2-ary lactate and derivative thereof.

Background technology:

The 2-ary lactate is a kind of important synthesis intermediates, such as being used for the synthetic of the analgesic widely anti-inflammation and analgesic drugs 2-of class arylpropionic acid, and as Naproxen Base, Ibuprofen BP/EP etc.The method of existing Synthetic 2-ary lactate mainly contains: and the methylating of 2-aryl-2-glycolic acid esters (J.Org.Chem.1977,42,2948-2950); Aryl ketones acid esters and the reaction of methyl Grignard reagent (Tetrahedron, 1987,4979-4988); The Grignard reagent of halogenated aryl hydrocarbon and pyruvate reaction (Tetrahedron, 1996,8257-8262); Phenol under the titanium tetrachloride effect with pyruvate reaction (Synthesis, 1984,760-763) preparation. the harsh and raw material costliness of first three kind condition of aforesaid method, the 4th kind of method only is confined to phenolic compound.

Summary of the invention:

The problem to be solved in the present invention provides a kind of convenience and the Synthetic 2-ary lactate of cheapness and the method for derivative thereof.

Method of the present invention is under a kind of Lewis acid effect, adding or do not adding under a kind of condition of alkali, the electron rich position of aromatic hydrocarbons directly and pyruvate carry out Friedel-Crafts reaction, the preparation 2-ary lactate of high yield.This method mild condition, raw material cheapness that is easy to get is suitable for industrialization.

The invention provides a kind of method of the 2-of being prepared as follows ary lactate:

Wherein Ar is the aryl that contains electron-donating group,

The described aryl that contains electron-donating group can be the aryl or the heteroaryl of electron donating group-substituted.Described aryl can be phenyl, naphthyl, also can for nitrogenous, oxygen, sulphur five to seven membered heterocyclic or its benzo ring, be single replacements, two replacements, trisubstituted furans, thiophene or indoles (substituting group can be silica-based, the p-toluenesulfonyl of the alkyl replacement of alkyl, the amino of the alkoxyl group of one to six carbon, one to six carbon, one to six carbon) as ArH; That described electron-donating group is recommended as that the alkyl of alkyl, the amino of the alkoxyl group of one to six carbon, one to six carbon, one to six carbon replaces is silica-based, p-toluenesulfonyl etc.; The aryl of described electron donating group-substituted comprises the aryl of one or more electron donating group-substituted.Described heteroaryl be nitrogenous, oxygen, sulphur five to seven membered heterocyclic or its benzo ring, as pyrroles, furans, thiophene, indoles etc.

R is the alkyl of one to six carbon.

Method of the present invention comprises the steps (1) or step (1) and (2):

(1) under a kind of Lewis acid effect, adds or do not add under the condition of alkali, the direct and pyruvate in the electron rich position of aromatic hydrocarbons ArH

Carry out Friedel-Crafts reaction and be prepared as follows the 2-ary lactate of structure:

Wherein Ar, R are as previously mentioned;

(2) gained 2-ary lactate restores and synthetic Naproxen Base of saponification and Ibuprofen BP/EP through routine reaction elimination dehydration when Ar is 2-methoxynaphthalene or second butylbenzene.

The concrete recommendation comprises the steps:

1. alkali is added in the organic solvent, add the pyruvate of electron rich aromatic hydrocarbons (Ar-H) and following structure again;

Ar and R are as previously mentioned;

2. then this system is cooled to subzero 25 and spends zero degree, begin to add Lewis acid under stirring;

3. spend to reaction between 50 degree subzero 25, after reacting completely reaction mixture is added in the water of the 0-5 degree that stirs the cancellation reaction;

4. the concentrated underpressure distillation of extraction liquid removes solvent and gets the product ary lactate.

Above-mentioned reinforced sequencing also can change, as earlier electron rich aromatic hydrocarbons (Ar-H) and Lewis acid adding reaction system being added pyruvate again.

When adding alkali, can be organic bases in the aforesaid method, as triethylamine, diethylamine, pyridine, piperidines, diisopropylethylamine is recommended as triethylamine; Also can be mineral alkali, as metal carbonate (salt of wormwood, yellow soda ash etc.), metal hydroxides (sodium hydroxide, potassium hydroxide etc.), metal oxide (calcium oxide, magnesium oxide, zinc oxide, aluminum oxide, titanium oxide, barium oxide etc.) is recommended as aluminum oxide.

Organic solvent is recommended as tetrahydrofuran (THF) in the aforesaid method, methylene dichloride, and oil of mirbane, chlorobenzene, ethylene dichloride, methyl tertiary butyl ether, Nitromethane 99Min., benzene, tetracol phenixin, perhaps the mixture of above solvent is recommended as ethylene dichloride.

Lewis acid is recommended as aluminum chloride in the aforesaid method, zinc chloride, iron(ic) chloride, titanium tetrachloride, nickelous chloride, tin tetrachloride, tindichloride, zirconium tetrachloride, boron trifluoride diethyl etherate, trimethylchlorosilane, trifluoromethanesulfonic acid zinc, copper trifluoromethanesulfcomposite, Bismuth triflate is recommended as titanium tetrachloride.

In the aforesaid method between each reactant the ratio of amount of substance be recommended as:

Aromatic hydrocarbons: pyruvate: alkali: Lewis acid=1.0: 1.0～1.5: 1.0～3.0: 0.5～2.5 recommendering folder invented technology are used for compound synthetic of following structure:

Reaction formula is:

Recommendation comprises the steps:

1. with in phenyl ethyl ether and pyruvate and the alkali adding organic solvent

2. then this system is cooled to subzero 50 and spends zero degree, begin to add Lewis acid under stirring;

3. spend to reaction between 5 degree subzero 50, after reacting completely reaction mixture is added in the water of the 0-5 degree that stirs the cancellation reaction;

4. the concentrated underpressure distillation of extraction liquid removes solvent and gets the product ary lactate.

The recommendering folder invented technology is used for compound synthetic of following structure:

Reaction formula is:

Comprise the steps:

1. with in 2-methoxynaphthalene and pyruvate and the alkali adding organic solvent

2. then this system is cooled to subzero 50 and spends zero degree, begin to add Lewis acid under stirring;

3. spend to reaction between 5 degree subzero 50, after reacting completely reaction mixture is added in the water of the 0-5 degree that stirs the cancellation reaction;

4. the concentrated underpressure distillation of extraction liquid removes solvent and gets the product ary lactate

The products obtained therefrom ary lactate is Naproxen Base (dehydration reduction saponification is popular response) through dehydration reduction saponification:

The recommendering folder invented technology is used for compound synthetic of following structure:

Reaction formula is:

Comprise the steps:

1. with in isobutyl-benzene and pyruvate and the alkali adding organic solvent

2. then this system is cooled to subzero 50 and spends zero degree, begin to add Lewis acid under stirring;

3. spend to reaction between 5 degree subzero 50, after reacting completely reaction mixture is added in the water of the 0-5 degree that stirs the cancellation reaction;

4. the concentrated underpressure distillation of extraction liquid removes solvent and gets the product ary lactate

The products obtained therefrom ary lactate is Ibuprofen BP/EP (dehydration reduction saponification is popular response) through dehydration reduction saponification:

Embodiment

Following examples help to understand this patent but this patent protection domain is not limited to this.

Embodiment 1

40 gram phenyl ethyl ethers and 40 gram Pyruvic Acid Ethyl esters are added in 400 milliliters of methylene dichloride, add 31 gram aluminum oxide again, then this system is cooled to subzero 45 degree, begin to add titanium tetrachloride, keep under the zero temperature 45, under this temperature, react then to subzero 20 degree.Till gas-chromatography tracking reaction raw materials no longer reduces.Spend to reaction between 5 degree subzero 10, after reacting completely reaction mixture is added in the water of the 0-5 degree that stirs the cancellation reaction.The concentrated underpressure distillation of extraction liquid removes solvent and gets product ary lactate 43 grams, yield 55%.

The order of addition(of ingredients) of the described embodiment of following table is with embodiment 1 or earlier electron rich aromatic hydrocarbons (Ar-H) and Lewis acid adding reaction system are added pyruvate again.

Embodiment	Raw material		Lewis acid	Alkali	Temperature of reaction	Solvent	Yield
								??2	Phenyl ethyl ether (1 mole)	Pyruvic Acid Ethyl ester (1.2 moles)	Tin tetrachloride (1.2 moles)	Triethylamine (2.0 moles)	??-25	Toluene	??56
??3	Methyl-phenoxide (1 mole)	Pyruvic Acid Ethyl ester (1.0 moles)	Trifluoromethanesulfonic acid zinc (1.1 moles)	Sodium hydroxide (2.0 moles)	??-30	Chlorobenzene	??71
								??4	2 one naphthol methyl ethers (1 mole)	Pyruvic Acid Methyl ester (1.5 moles)	Titanium tetrachloride (0.8 mole)	Aluminum oxide (1.5 moles)	??-5	Oil of mirbane	??60
??5	Isobuytel Benzene (1 mole)	Pyruvic Acid Ethyl ester (1.1 moles)	Tin tetrachloride (0.5 mole)	Aluminum oxide (1.1 moles)	??-15	Ethylene dichloride	??53
								??6	N one p-toluenesulfonyl indoles (1 mole)	Pyruvic Acid Ethyl ester (1.2 moles)	Aluminum chloride (0.9 mole)	Aluminum oxide (1.1 moles)	??-25	Tetrahydrofuran (THF)	??89
??7	Thiophene (1 mole)	Pyruvic Acid Ethyl ester (1.1 moles)	Titanium tetrachloride (1.1 moles)	Aluminum oxide (1.2 moles)	??-30	Benzene	??42
								??8	Furans (1 mole)	Pyruvic Acid Ethyl ester (1.1 moles)	Tin tetrachloride (0.5 mole)	Aluminum oxide (1.2 moles)	??-30	Benzene	??31
??9	Veratrole (1 mole)	Pyruvic Acid Methyl ester (1.5 moles)	Tin tetrachloride (0.6 mole)	Pyridine (3.0 moles)	??-40	Benzene	??78
								??10	P-dimethyoxy benzene (1 mole)	Pyruvic Acid Methyl ester (1.5 moles)	Iron(ic) chloride (2.5 moles)	Yellow soda ash (1.0 moles)	??-45	Stupid	??82
??11	To dimethoxy	Pyruvic Acid Methyl ester	Iron(ic) chloride	Do not add alkali	??-45	Benzene	??35

Base benzene (1 mole)

(1.5 moles)

(2.5 moles)

The compound characterization data:

FTIR(neat)：3523，2983，1721，1245cm ^-1； ¹H?NMR(CDCl ₃，300MHz)δ＝7.45(d，J＝9.0Hz，2H)，6.87(d，J＝8.7Hz，2H)，4.02(q，J＝7.0Hz，2H)，3.76(s，3H)，3.72(s，1H)，1.76(s，3H)，1.41(t，J＝7.0Hz，3H)； ¹³C?NMR(CDCl ₃，75MHz)δ＝176.2，158.4，134.5，126.3，113.9，75.3，63.2，53.0，26.5，14.7；MS(EI)m/e?224(M+，5.9)，165(100)，43(36.9)；Anal.Calcd?for?C ₁₂H ₁₆O ₄：C，64.27；H，7.19.Found：C，64.11；H，711

FTIR(neat)：3506，2983，1728，1247cm ^-1； ¹H?NMR(CDCl ₃，300MHz)δ＝7.46(d，J＝9.0Hz，2H)，6.87(d，J＝8.7Hz，2H)，4.25(q，J＝7.1Hz，2H)，4.02(q，J＝7.0Hz，2H)，3.77(s，3H)，3.72(s，1H)，1.75(s，3H)，1.41(t，J＝7.0Hz，3H)，1.27(t，J＝7.1Hz，3H)； ¹³C?NMR(CDCl ₃，75MHz)δ＝175.6，158.3，134.7，126.3，113.9，75.1，63.2，62.0，26.5，14.6，13.9；MS(EI)m/e?238(M+，3.5)，165(100)，43(59.7)；Anal.Calcd?forC ₁₃H ₁₈O ₄：C，65.53；H，7.61.Found：C，65.59；H，7.66.

FTIR(neat)：3516，2959，1729，1255cm ^-1； ¹H?NMR(CDCl ₃，300MHz)δ＝7.45(d，J＝8.8Hz，2H)，6.87(d，J＝8.6Hz，2H)，3.87(s，3H)，3.78(s，3H)，3.75(s，3H)，1.76(s，3H)； ¹³C?NMR(CDCl ₃，75MHz)δ＝176.2，159.0，134.7，126.4，113.5，75.3，55.1，53.1，26.6；MS(EI)m/e?210(M+，2.7)，151(70.6)，43(100)；Anal.Calcd?for?C ₁₁H ₁₄O ₄：C，62.85；H，6.71.Found：C，62.80；H，6.52.

FTIR(neat)：3502，2954，1735，1261cm ^-1； ¹H?NMR(CDCl ₃，300MHz)δ＝7.06(d，J＝2.2Hz，1H)，7.02(d，J＝2.0Hz，1H)，6.78(d，J＝2.3Hz，1H)，3.85(s，1H)，3.83(s，3H)，3.81(s，3H)，3.71(s，3H)，1.72(s，3H)； ¹³C?NMR(CDCl ₃，75MHz)δ＝176.0，148.5，148.4，135.2，117.4，110.6，108.4，75.4，55.7，53.1，26.6；MS(EI)m/e?240(M+，37.6)，223(96.9)，181(100)，43(92.2)；Anal.Calcd?for?C ₁₂H ₁₆O ₅：C，59.99；H，6.71.Found：C，60.02；H，6.82.

FTIR(neat)：3501，2957，1743，1232cm ^-1； ¹H?NMR(CDCl ₃，300MHz)δ＝7.01(s，1H)，6.78(s，2H)，4.07(s，1H)，3.73(s，3H)，3.66(s，3H)，3.58(s，3H)，1.70(s，3H)； ¹³C?NMR(CDCl ₃，75MHz)δ＝176.1，153.5，150.6，132.2，113.2，112.7，111.9，74.0，55.9，55.6，52.5，24.1；MS(EI)m/e?240(M+，13.2)，223(2.9)，181(99.5)，43(100)；Anal.Calcd?for?C ₁₂H ₁₆O ₅：C，59.99；H，6.71.Found：C，59.74；H，6.61.

FTIR(KBr)：3511，2959，1735，1372cm ^-1； ¹H?NMR(CDCl ₃，300MHz)δ＝7.95(d，J＝8.6Hz，1H)，7.76(d，J＝8.2Hz，2H)，7.70(d，J＝8.0Hz，1H)，7.65(s，1H)，7.32-7.18(m，4H)，3.93(s，1H)，3.73(s，3H)，2.31(s，3H)，1.87(s，3H)； ¹³CNMR(CDCl ₃，75MHz)δ＝175.7，145.1，135.4，134.9，129.9，128.1，126.9，124.7，124.1，123.7，123.3，121.2，113.5，72.6，53.4，25.9，21.5；MS(EI)m/e?373(M+，6.5)，355(10.0)，314(93.9)，155(38.7)，91(100)；Anal.Calcd?for?C ₁₉H ₁₉NO ₅S：C，61.11；H，5.13；N，3.75.Found：C，61.13；H，5.14；N，3.57.

FTIR(neat)：3524，2959，1733，1259cm ^-1； ¹H?NMR(CDCl ₃，300MHz)δ＝7.76(dd，J＝8.8?and?0.8Hz，1H)，7.47(dd，J＝8.3?and?0.8Hz，1H)，7.19(s，1H)，7.15-7.10(m，2H)，3.82(s，1H)，3.74(s，3H)，1.91(s，3H)，0.92(s，9H)，0.59(s，6H)； ¹³CNMR(CDCl ₃，75MHz)δ＝176.4，141.8，128.3，128.0，121.3，120.1，119.9，119.7，113.9，72.9，52.8，26.1，25.9，19.2，-4.1；MS(EI)m/e?333(M+，10.5)，217(100)；Anal.Calcd?for?C ₁₈H ₂₇NO ₃Si：C，64.83；H，8.16；N，4.20.Found：C，64.63；H，8.14；N，4.37.

FTIR(neat)：3534，2959，1750cm ^-1； ¹H?NMR(CDCl ₃，300MHz)δ＝6.42(d，J＝4.8Hz，1H)，6.30(d，J＝8.3，1H)，5.90(d，J＝4.8Hz，1H)，5.0(br，1H)，3.82(s，1H)，3.74(s，3H)，1.91(s，3H)； ¹³C?NMR(CDCl ₃，75MHz)δ＝168.7，118.8，117.3，116.1，114.0，78.9，52.8，25.4；MS(EI)m/e?169(M+，100)；Anal.Calcd?forC ₈H ₁₁NO ₃：C，56.80；H，6.55；N，8.28.Found：C，56.63；H，6.34；N，8.37.

Claims (10)

1. the method for a Synthetic 2-ary lactate and Naproxen Base and Ibuprofen BP/EP is characterized in that comprising the steps (1) or step (1) and (2):

(1) under a kind of Lewis acid effect, adds or do not add under the condition of alkali, the direct and pyruvate in the electron rich position of aromatic hydrocarbons ArH

Carry out Friedel-Crafts reaction and be prepared as follows the 2-ary lactate of structure:

Wherein Ar is the aryl that contains electron-donating group, and R is the alkyl that contains one to six carbon;

(2) gained 2-ary lactate restores and synthetic Naproxen Base of saponification and Ibuprofen BP/EP through eliminating dehydration when Ar is 2-methoxynaphthalene or second butylbenzene.

2. the method for claim 1, it is characterized in that the described aryl Ar that contains electron-donating group is the phenyl of electron donating group-substituted, the naphthyl of electron donating group-substituted, nitrogenous, the oxygen of electron donating group-substituted, sulphur five to seven membered heterocyclic or its benzo ring, or heteroaryl.

3. the method for claim 1 is characterized in that described electron-donating group is silica-based, the p-toluenesulfonyl that the alkyl of alkyl, the amino of the alkoxyl group of one to six carbon, one to six carbon, one to six carbon replaces.

4. the method for claim 1 is characterized in that described step (1) comprising:

A. alkali is added in the organic solvent, add the pyruvate of electron rich aromatic hydrocarbons (Ar-H) and following structure again; Ar and R are according to claim 1;

B. then this system is cooled to subzero 25 and spends zero degree, begin to add Lewis acid under stirring; Perhaps earlier electron rich aromatic hydrocarbons (Ar-H) and Lewis acid adding reaction system are added pyruvate again;

C. spend to reaction between 50 degree subzero 25, after reacting completely reaction mixture is added in the water of the 0-5 degree that stirs the cancellation reaction;

D. the concentrated underpressure distillation of extraction liquid removes solvent and gets the product ary lactate.

5. as claim 1 or 4 described methods, it is characterized in that described Lewis acid is: aluminum chloride, zinc chloride, iron(ic) chloride, titanium tetrachloride, nickelous chloride, tin tetrachloride, zirconium tetrachloride, tindichloride, boron trifluoride diethyl etherate, trimethylchlorosilane, trifluoromethanesulfonic acid zinc, copper trifluoromethanesulfcomposite, Bismuth triflate.Described alkali is triethylamine, diethylamine, pyridine, piperidines, diisopropylethylamine, alkali-metal carbonate, alkali-metal oxyhydroxide, metal oxide.

6. as claim 1 or 4 described methods, it is characterized in that described being reflected in the organic solvent carry out, described organic solvent is a tetrahydrofuran (THF), methylene dichloride, oil of mirbane, chlorobenzene, ethylene dichloride, methyl tertiary butyl ether, Nitromethane 99Min., benzene, tetracol phenixin, the perhaps mixture of above solvent.

7. as claim 1 or 4 described methods, it is characterized in that the ratio of amount of substance between the described reactant is: aromatic hydrocarbons: pyruvate: alkali: Lewis acid=1.0: 1.0～1.5: 1.0～3.0: 0.5～2.5.

8. the method for claim 1 is characterized in that being used for compound synthetic of following structure:

Comprise the steps:

(1). in phenyl ethyl ether and pyruvate and alkali adding organic solvent

(2). then this system is cooled to subzero 50 and spends zero degree, begin to add Lewis acid under stirring;

(3). spend to reaction between 5 degree subzero 50, after reacting completely reaction mixture is added in the water of the 0-5 degree that stirs the cancellation reaction;

(4). the concentrated underpressure distillation of extraction liquid removes solvent and gets the product ary lactate.

9. the method for claim 1 is characterized in that being used for compound synthetic of following structure:

Comprise the steps:

(1). in 2-methoxynaphthalene and pyruvate and alkali adding organic solvent

(2). then this system is cooled to subzero 50 and spends zero degree, begin to add Lewis acid under stirring;

(3). spend to reaction between 5 degree subzero 50, after reacting completely reaction mixture is added in the water of the 0-5 degree that stirs the cancellation reaction;

(4). the concentrated underpressure distillation of extraction liquid removes solvent and gets the product ary lactate

(5) the products obtained therefrom ary lactate is Naproxen Base through routine reaction dehydration reduction saponification.

10. the method for claim 1 is characterized in that being used for compound synthetic of following structure:

Comprise the steps:

(1). in isobutyl-benzene and pyruvate and alkali adding organic solvent

(2). then this system is cooled to subzero 50 and spends zero degree, begin to add Lewis acid under stirring;

(3). spend to reaction between 5 degree subzero 50, after reacting completely reaction mixture is added in the water of the 0-5 degree that stirs the cancellation reaction;

(4). the concentrated underpressure distillation of extraction liquid removes solvent and gets the product ary lactate;

(5). the products obtained therefrom ary lactate is Ibuprofen BP/EP through routine reaction dehydration reduction saponification.