WO2000026177A1

WO2000026177A1 - Synthesis of ethyl bromopyruvate

Info

Publication number: WO2000026177A1
Application number: PCT/US1999/025029
Authority: WO
Inventors: Yuri A. Lapin; Karl E. Reineke; Kevin B. Kunnen; Ignacio H. Sanchez
Original assignee: Great Lakes Chemical Corporation
Priority date: 1998-10-29
Filing date: 1999-10-27
Publication date: 2000-05-11

Abstract

A process to manufacture ethyl bromopyruvate from ethyl pyruvate by reacting ethyl pyruvate with bromine chloride. The reaction may be carried out by contacting ethyl pyruvate with pre-formed bromine chloride or with bromine chloride generated in situ. Subsequent purification of the crude product mixture produces ethyl bromopyruvate in high purity.

Description

SYNTHESIS OF ETHYL BROMOPYRUVATE

This invention relates to a process for the manufacture of ethyl bromopyruvate. More specifically, this invention relates to a single-step synthesis of high purity ethyl bromopyruvate from ethyl pyruvate and bromine chloride.

I. BACKGROUND OF THE INVENTION

Ethyl bromopyruvate (EBPY) is an intermediate with application in the manufacture of pharmaceuticals and agricultural chemicals. For example, EBPY may be used in the preparation of 2-ω-aminoalkyl and 2-ω- sulphanilamidoalkyl derivatives of thiazole and pyrimidine, which are potential bacterial inhibitors. See Alan A. Goldberg δe William Kelly, Synthesis of the 2-ω-Aminoalkyl and 2-ω-Sulphanilamidoalkyl Derivatives of Thiazole and Pyrimidine, J. Chem. Soc. 1372 (1947), the disclosure of which is specifically incorporated into this specification by reference.

Previously, EBPY was prepared by oxidizing and brominating ethyl lactate with N-bromosuccinimide (Equation 1) or 1, 3-dibromo-5, 5-dimethyl-hydantoin (Equation 2) . OH 0 CH₃CHC0₂C₂H₅ + BrCH₂CHC0₂C₂H₅

Equation 1

Equation 2

These prior reactions are described in Paul F. Kruse, Nathan Geurkink, and Ken L. Grist, New Syntheses of β-Bromo-α-keto Esters, Ethyl Phenylgloxylate and Phenacyl Bromide Using N-Bromo-succinimide, 76 J. Amer. Chem. Soc. 5796 (1954); Huang, J. ; Xu, Z . ; Fang, G. Huaxue Tongbao, 1994, 5, 35; and Romanian Patent RO 96382 Bl 890530 to Cadis et al . , the disclosures of which are specifically incorporated into this specification by reference.

These prior reactions have several shortcomings. First, the reagents must be refluxed in restricted and/or expensive solvents such as carbon tetrachloride. Second, each reaction produces hydrogen bromide, which degrades EBPY, and third, both reactions must be performed at elevated temperatures such as 50 to 65°C, which accelerate the effects of the HBr on EBPY. Previously, EBPY was also prepared by brominating ethyl pyruvate with elemental bromine.

0 0

CH₃C IIC0₂C₂H₅ + Br₂ >- BrCH₂CIIHC0₂C₂H5 + HBr

Equat ion 3

This prior reaction is described with and without the use of solvent in S. Archer & Margaret G. Pratt, Δ- (3, 4-Dicarboxy) -furanvaleric and -acetic Acids, 66 Amer. Chem. Soc. 1656 (1944), and E.T. Borrows & D.O. Holland, The Synthesis of Pyrrocoline-2-carboxylic Acid: A New Route to Pyrrocoline, J. Chem. Soc. 673 (1947), the disclosures of which are specifically incorporated into this specification by reference. This prior reaction has shortcomings that are similar to the other prior reactions. First, the reaction is performed at elevated temperatures, usually in the range of 50 to 65°C. Second, residual HBr degrades the product, and third, the overall selectivity (the ratio between the yield of the product and the conversion of the starting compound) of the process is only in the range of 70 to 75%. As a result, commercially available ethyl bromopyruvate is at best only about 90% pure, largely resulting from the effects of acidic and/or basic impurities that are left in the EBPY from previously known manufacturing processes. These impurities not only degrade the EBPY, but also facilitate its disproportionation into ethyl pyruvate and ethyl dibromopyruvate as well as EBPY' s condensation into other products.

What is needed is a process to manufacture EBPY that offers easily removed by-products that neither degrade EBPY nor change EBPY' s effectiveness as a reactant. The following invention is one solution to this problem.

II. SUMMARY OF THE INVENTION

In one aspect, this invention is a process to synthesize ethyl bromopyruvate by reacting ethyl pyruvate and bromine chloride to form a product containing hydrogen chloride and ethyl bromopyruvate. In another aspect, this invention is a process to synthesize ethyl bromopyruvate by contacting ethyl pyruvate, bromine and chlorine under conditions that form ethyl bromopyruvate and a hydrogen chloride byproduct. In yet another aspect, this invention is a process to synthesize ethyl bromopyruvate by reacting bromine and chlorine to form bromine chloride; reacting the bromine chloride with ethyl pyruvate to form a product including ethyl bromopyruvate and hydrogen chloride; contacting the product with an inert gas to remove a portion of the hydrogen chloride; adding a compound to the crude ethyl bromopyruvate product that boils at a higher temperature than pure ethyl bromopyruvate; distilling the crude ethyl bromopyruvate product; and recovering purified ethyl bromopyruvate from the distillation. An advantage of this process is that it is performed at a lower temperature than prior methods to produce ethyl bromopyruvate.

Another advantage of this invention is that the ethyl bromopyruvate obtained from this reaction has improved stability during storage, largely resulting from the fact that hydrogen chloride is produced as a by-product rather than hydrogen bromide.

A feature of this invention is that it produces hydrogen chloride as a by-product, which is more easily removed from ethyl bromopyruvate than the hydrogen bromide by-product produced in prior methods.

Another feature of this invention is that it can be used to prepare ethyl bromopyruvate in purities which were not previously attainable using prior syntheses .

III. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Specific language is used to describe several embodiments of the present invention for the purpose of promoting an understanding of the principles of the invention. However, it must be understood that no limitation of the scope of the present invention is intended by using this specific language. Any alteration and further modification of the described procedure and any application of the principles of the present invention that normally occur to one skilled in the art to which the present invention pertains are also intended. In one embodiment, the present invention is a method to prepare ethyl bromopyruvate by reacting ethyl pyruvate and bromine chloride according to the following equation.

0 0

CH₃CC0₂C₂H₅ + BrCl >- BrCH₂CHC0₂C₂H5 + HC1

Equation 4

The first reactant, ethyl pyruvate, is widely known and commercially available from sources such as Toray International, Inc., the Alfa Aesar Co., DSM Chemie Linz and Penta Manufacturing Company, or the Aldrich Chemical Company, Inc. Ethyl pyruvate is typically produced by a catalyzed reaction of diethyl tartrate over silica-supported potassium disulfate, or by oxidizing ethyl lactates with hydrogen peroxide. These reactions are respectively disclosed in Sugiyama, Fukunaga, Kawashiro, Hayashi, Bull. Chem. Soc. Jpn., 1992, 65(8), 2083-5; and Christides, Y.; Vallejos, J.C. European Pat. Appl . EP 326470; 1989, the disclosures of which are specifically incorporated into this specification by reference.

The second reactant, bromine chloride, can either be supplied to the reaction or generated in the reaction medium. If supplied to the reaction, bromine chloride can be initially prepared by contacting chlorine and bromine under conditions that allow the two to react, for example, by bubbling chlorine gas through elemental bromine. During the addition of chlorine, the temperature of the mixture is preferably maintained below the boiling point of bromine chloride. A suitable range is from about -20 to about 25°C, with about -10 to about 10° C being preferred. Suitable molar ratios of chlorine to bromine are those sufficient to convert the bromine to bromine chloride. Accordingly, at least an equimolar amount of chlorine is preferably used to react with all the bromine that is present, however, a slight molar excess of chlorine is generally preferred, for example, up to about 1.04 moles of chlorine per mole of bromine. EBPY can then be prepared by contacting ethyl pyruvate and bromine chloride under reaction conditions that allow the two compounds to react. The temperature of the mixture is preferably maintained below the boiling point of bromine chloride. For example, one suitable range at atmospheric pressure is from about - 20 to about 25°C, with about -10 to about 10°C being preferred. Suitable molar ratios of the reactants are preferably those sufficient to convert all the ethyl pyruvate to EBPY. Accordingly, at least an equimolar amount of bromine chloride is preferably used to react with all the ethyl pyruvate that is present. However, a molar excess of bromine chloride is generally preferred, for example, up to about 1.25 moles of bromine chloride per mole of ethyl pyruvate.

In another embodiment, the present invention is a method to prepare ethyl bromopyruvate by contacting ethyl pyruvate, bromine and chlorine. This reaction is largely the same as that previously described between bromine chloride and ethyl pyruvate, except that bromine and chlorine react to generate bromine chloride in the presence of the ethyl pyruvate.

In this embodiment, it is also preferable that the reaction conditions are such that a complete conversion of ethyl pyruvate into EBPY is achieved. Accordingly, the temperature of the mixture is preferably maintained below the boiling point of bromine chloride. For example, one suitable range at atmospheric pressure is from about -20 and about 25°C, with about -10 to 10°C being preferred. Suitable molar ratios of the reactants are preferably those sufficient to convert all the ethyl pyruvate to EBPY. Hence, at least a stoichiometric quantity of ethyl pyruvate, bromine and chlorine in a respective molar ratio of about 1:0.5:0.5 is generally used. However, a slight molar excess of bromine and chlorine is generally preferred, for example, a respective molar ratio of ethyl pyruvate, bromine and chlorine of about 1:0.625:0.65. Once the formation of EBPY is complete, preferably most of the hydrogen chloride (HC1) produced in the reaction is then removed from the product mixture. In one embodiment, this may be accomplished by subsurface sparging with a non-reactive gas, such as nitrogen, until HC1 no longer escapes from the product mixture.

After most of the HC1 is removed, the EBPY is then preferably distilled with or without the aid of a high boiling hydrocarbon additive, and preferably under reduced pressure. A suitable vacuum is one that efficiently removes the more volatile compounds and allows the collection of not less than 90-wt% EBPY. A typical vacuum is in the range between about 1 mmHg and about 25 mmHg, with a pressure of about 15 mmHg being preferred. If a high boiling chaser is used, hydrocarbon additives that have boiling points above the collection temperature of EBPY are preferred, of which one example is commercially available eicosane, CH₃(CH₂)ι₈CH₃, CAS Number 112-95-8. The amount of high boiling chaser which is used in the distillation may range up to about 10-wt%; however, only about 5-wt% is preferred.

IV. EXAMPLES

The following examples are illustrative of the invention. Example 1

Ethyl pyruvate (109.55mL, 116.12g, lmol) was charged into a reaction flask. Bromine (25.76mL,

79.91g, 0.5mol) was charged into a jacketed addition funnel. Using a circulating cooling bath, the bromine in the addition funnel and the ethyl pyruvate in the flask were cooled to -4° ± 2°C. Chlorine gas (37.00g, 0.52mol) was added to the bromine through a dip tube. The speed of the addition was adjusted to keep the internal temperature in the jacketed addition funnel at -4° ± 2°C. The resulting bromine chloride was slowly added to the ethyl pyruvate. The internal temperature was maintained at -2° ± 2°C in the reaction flask during the addition. After the addition was complete, the reaction mixture was stirred for 2 hours at 2°C and then allowed to warm to room temperature. A subsurface nitrogen sparge was used for 3.5 hours to remove the bulk of the HCl and to leave 181g (80% purity by GC, area % analysis) of EBPY. The crude material was distilled through a 5-plate Oldershaw column with a reflux ratio of 2 to 1 at 15 mmHg in the presence of 9.1g (5-wt%) of eicosane to give 139g (96% purity, 69% corrected yield) of EBPY. The main fraction was collected at 93-94°C. Example 2

79.91g, 0.5mol) was charged into a jacketed addition funnel. Using a circulating cooling bath, the bromine in the addition funnel and the ethyl pyruvate in the flask were cooled to -4° ± 2°C. Initially, about 7mL of the bromine was added to the ethyl pyruvate then chlorine was slowly bubbled through the reaction mixture while the rest of the bromine was added. The speed of the simultaneous addition of bromine and chlorine gas (37.00g, 0.52mol) to ethyl pyruvate was adjusted to keep the internal temperature at -2° ± 2°C in the reaction flask and to finish the addition of the reagents at the same time. After the addition was complete, the reaction mixture was stirred for 2 hours at 2°C and then allowed to warm to room temperature. A subsurface nitrogen sparge was used for 3.5 hours to remove the bulk of the HCl. The crude product mixture was then quickly (during 1 hour) distilled through a 5- plate Oldershaw column at 22-25 mmHg to give 130g (90% purity, 60% corrected yield) of EBPY. The main fraction was collected at 104-108°C.

Example 3

Ethyl pyruvate (109.55mL, 116.12g, lmol) was charged into a reaction flask and its temperature was reduced to -23°C. Bromine (25.76mL, 79.91g, 0.5mol) was added in one portion at the same temperature. Chlorine gas (35.45g, 0.50mol) was then bubbled through the reaction mixture. The speed of the addition was adjusted to keep the internal temperature at -9°C. After the addition was complete the temperature was allowed to rise to 0°C and was maintained for 1 hour. Then the reaction mixture was slowly heated to room temperature over a 1-hour period. The reaction mixture was subjected to vacuum treatment, that is, it was kept at 20mmHg for 2 hours to remove the bulk of HCl, and then quickly (during 1 hour) distilled at 12 mmHg to give 154g (92% purity, 72% corrected yield) of EBPY. The main fraction was collected at 85-88°C.

Example 4

Ethyl pyruvate (109.55mL, 116.12g, lmol) was charged into a reaction flask. Bromine (25.76mL, 79.91g, 0.5mol) was charged into a jacketed addition funnel. Using a circulating cooling bath, the bromine in the addition funnel and the ethyl pyruvate in the flask were cooled to -4° ± 2°C. Chlorine gas (37.00g, 0.52mol) was added through a dip tube to the bromine. The speed of the addition was adjusted to keep the internal temperature in the jacketed addition funnel to -4° ± 2°C. The resulting bromine chloride was slowly added to the ethyl pyruvate. The internal temperature was maintained at -2° ± 2°C in the reaction flask during the addition. After the addition was complete, the reaction mixture was stirred for 2 hours at 2°C and then allowed to warm to room temperature. A subsurface nitrogen sparge was used for 3.5 hours to remove the bulk of the HCl and to leave 181g (80% purity by GC, area % analysis) of EBPY. The crude product mixture was quickly (during 1 hour) distilled through a 5-plate Oldershaw column at 22-25 mmHg to give 139.9g (90% purity, 64% corrected yield) of EBPY. The main fraction was collected at 104-108°C.

Example 5

Ethyl pyruvate (109.55mL, 116.12g, lmol) was charged into a reaction flask. Bromine (25.76mL, 79.91g, 0.5mol) was charged into a jacketed addition funnel. Using a circulating cooling bath, the bromine in the addition funnel and the ethyl pyruvate in the flask were cooled at -4° ± 2°C. Chlorine gas (35.45g, 0.5mol) was added through a dip tube to the bromine. The speed of the addition was adjusted to keep the internal temperature in the jacketed addition funnel at -4° ± 2°C. The resulting bromine chloride was slowly added to the ethyl pyruvate. The internal temperature was maintained at -2° ± 2°C in the reaction flask during the addition. After the addition was complete, the reaction mixture was stirred for 2 hours at 2°C and then allowed to warm to room temperature. A subsurface nitrogen sparge was used for 3.5 hours to remove the bulk of the HCl. The crude product mixture was slowly (during 9 hours) distilled through a 5-plate Oldershaw column at 13 mmHg with a reflux ratio of 5 to 1 to give 105g (88% purity, 47% corrected yield) of EBPY. The main fraction was collected at 90-92°C and contained 8% (by GC area % analysis) of ethyl 3-bromo-2- ethoxyacrylate .

Example 6

Ethyl pyruvate (109.55mL, 116.12g, lmol) was charged into a reaction flask. Bromine (25.76mL, 79.91g, 0.5mol) was charged into a jacketed addition funnel. Using a circulating cooling bath, the bromine in the addition funnel and the ethyl pyruvate in the flask were cooled to -4° ± 2°C. Chlorine gas (37.00g, 0.52mol) was added through a dip tube to the bromine. The speed of the addition was adjusted to keep the internal temperature in the jacketed addition funnel to -4° ± 2°C. The resulting bromine chloride was slowly added to the ethyl pyruvate. The internal temperature was maintained at -2° ± 2°C in the reaction flask during the addition. After the addition was complete, the reaction mixture was stirred for 2 hours at 2°C and then allowed to warm to room temperature. A subsurface nitrogen sparge was used for 3.5 hours to remove the bulk of the HCl and to leave 181g (80% purity by GC, area % analysis) of ethyl bromopyruvate. The crude product mixture was slowly (during 8 hours) distilled through a 5-plate Oldershaw column at 15 mmHg in the presence of 9.1g (5-wt%) of paraffin to give 139g (96% purity, 69% corrected yield) of ethyl bromopyruvate. The main fraction was collected at 93-94°C.

While the invention has been illustrated and described in detail in the examples and foregoing description, the same is to be considered as illustrative and not restrictive in character, it being understood that only the preferred embodiments have been shown and described and that all changes and modifications that come within the spirit of the invention are desired to be protected.

Claims

We claim:

1. A process to synthesize alkyl bromopyruvates comprising reacting a C₁-C5 alkyl pyruvate and bromine chloride to form a product containing hydrogen chloride and alkyl bromopyruvate.

2. The process of claim 1 and wherein said alkyl pyruvate is ethyl pyruvate.

3. The process of claim 1 and further comprising reacting bromine and chlorine to form said bromine chloride.

4. The process of claim 1 and further comprising contacting said product with an inert gas, whereby said inert gas removes at least a portion of said hydrogen chloride from said product.

5. The process of claim 4 and wherein said inert gas is nitrogen.

6. The process of claim 2 and further comprising distilling said product and recovering said ethyl bromopyruvate .

7. The process of claim 6 and wherein said distilling is performed at subatmospheric pressure.

8. The process of claim 6 and wherein a continuous distillation is used.

9. The process of claim 6, wherein a batch distillation is used.

10. The process of claim 6 and further including adding to said product an organic compound that boils at a higher temperature than ethyl bromopyruvate, whereby said organic compound suppresses side reactions, acts as a distillation chaser and increases the boiling point of the distilland in said distillation.

11. A process to synthesize ethyl bromopyruvate comprising contacting ethyl pyruvate, bromine and chlorine under conditions to form a product containing ethyl bromopyruvate.

12. The process of claim 11 and further comprising contacting said product with an inert gas, whereby said inert gas removes at least a portion of said hydrogen chloride from said product.

13. The process of claim 12 and wherein said inert gas is nitrogen.

14. The process of claim 12 and further comprising distilling said product.

15. The process of claim 14, where said distilling is performed at subatmospheric pressure.

16. The process of claim 14, wherein a continuous distillation is used.

17. The process of claim 14, wherein a batch distillation is used.

18. The process of claim 14, including adding an organic compound that boils at a higher temperature than ethyl bromopyruvate to said product, whereby said organic compound supresses side reactions, acts as a distillation chaser and increases the boiling point of the distilland in said distillation.

19. A process to synthesize ethyl bromopyruvate comprising:

(a) reacting bromine and chlorine to form bromine chloride; (b) reacting said bromine chloride with ethyl pyruvate to form a product containing hydrogen chloride and ethyl bromopyruvate;

(c) contacting said product with an inert gas, whereby said inert gas removes at least a portion of said hydrogen chloride from said product;

(d) adding a compound to said product that boils at a higher temperature than ethyl bromopyruvate, whereby said organic compound suppresses side reactions, acts as a distillation chaser and increases the boiling point of the distilland formed upon distillation of said product; (e) distilling said product and added compound; and (f) recovering ethyl bromopyruvate from said distillation.

20. The process of claim 19, wherein said inert gas is nitrogen.

21. The process of claim 19, wherein said distilling is performed at subatmospheric pressure.