Patent Grant
8658589
1. Field of the Invention
The invention concerns fatty acyl amido based surfactant concentrates.
2. The Related Art
Fatty acyl amido salts are desirable surfactants. They have good water solubility, good detergency and foaming properties. Most especially they are mild to the skin. Unfortunately the amount of and extent of their usage is limited because they are expensive to produce.
The most traditional and present commercial route to fatty acyl amido carboxylic salts is found in U.S. Pat. No. 6,703,517 (Hattori et al.). Synthesis is achieved by reacting the amino acid with activated fatty acid derivatives, especially fatty acyl chlorides. The process requires a mole equivalent of alkali to remove the hydrogen chloride byproduct of the reaction. There are evident waste disposal issues with the byproducts and the added cost of chloride is not fully recoverable. A still further problem is incompatibility of unsaturated fatty acids with the harsh reaction conditions. Unsaturates decompose and can form color bodies.
Direct esterification and interesterification are routes which also have been previously investigated. US Patent Application Publication No. 2006/0239952 A1 (Hattori) describes a reaction between a neutral amino acid and a long chain fatty acid catalyzed by an alkaline substance such as sodium hydroxide or potassium hydroxide. For instance, the reaction between glycine and lauric acid produces the acylated products lauroylglycine and lauroylglycylglycine. Significant byproducts include the non-acylated forms such as glycylglycine and glycyldiketopiperazine, as well as unreacted glycine. The reaction is said to be highly efficient (yield of the acylated forms) but this results because the ratio of lauric acid starting material to glycine is extremely high.
DE 44 08 957 A1 (BASF AG) reports N-acyl aminocarboxylic acids prepared by reaction of a suspension of solid anhydrous alkali metal salts of aminocarboxylic acids and an appropriate carboxylic acid or ester. Catalytic amounts of strong base are added to the suspension to promote the reaction. Illustrative is the reaction of equimolar amounts of lauric acid and anhydrous sodium sarcosine heated together molten at 200° C. in the presence of a molar equivalent of sodium hydroxide. Although the yields are high, the resultant product is highly colored.
None of the known esterification or interesterification processes are without a disadvantage. Many require relatively high temperatures and/or strong alkali to progress the reaction. These conditions promote side reactions of the amino acids with themselves rather than with the fatty acylating reagent. These competing reactions squander expensive amino acid starting reagent and require removal cleanup steps. Yields are also adversely affected. Furthermore, the necessary conditions for reaction in the known art are too harsh for the simpler amino acids.
A problem common to most acyl amido compounds produced by the known methods is discoloration of the reaction resultant concentrate. Small amounts of colored byproducts have significant visual impact.
A concentrate of C8-C22 acyl amido compounds is provided prepared by a process which includes:
In our efforts to find an improved synthesis of C8-C22 acyl amido carboxylates and sulfonates, we have discovered that the resultant reaction masses are without further workup excellent surfactant concentrates. Now we can obtain foaming surfactant concentrates based on C8-C22 acyl amido carboxylic or sulfonic acids or salts thereof, in combination with polyol and fatty acids. These concentrates are relatively free of byproduct forming color bodies. The concentrate can be used as a cleanser per se or incorporated (dissolved or suspended) in an aqueous or non-aqueous liquid or bar with other formulation ingredients.
The concentrates have become available because of a relatively mild interesterification reaction that has achieved good yields of a surfactant active. An important element in both the interesterification reaction and the resultant concentrate product is that of a significant polyol presence.
Accordingly, concentrates of the present invention will contain C8-C22 acyl amido compounds of structure (II) in amounts ranging from 40 to 90%, preferably from 45 to 80%, and optimally from 50 to 75% by weight of the concentrate.
A polyol will also be present both in the concentrate and as a reaction medium for the interesterification leading to the concentrate. Illustrative polyols are glycerol, propylene glycol, dipropylene glycol, pentylene glycol, butylene glycol, isobutylene glycol and combinations thereof. Most preferred are glycerol and propylene glycol. Amounts of the polyol in the concentrate may range from 10 to 60%, preferably from 20 to 50%, and optimally from 25 to 45% by weight.
Another material present in the concentrate is C8-C22 fatty acids. Illustrative fatty acids include lauric, myristic, palmitic, stearic, oleic, linoleic, behenic acids and combinations thereof. Amounts of the fatty acids in the concentrate may range from about 1 to about 20%, preferably from 2 to 15%, and optimally from 4 to 10% by weight.
The concentrates of the present invention are made by the interesterification reaction between an amino compound or salt thereof and a fatty acid ester in a polyol reaction medium. Glycerol is the most preferred medium.
A first reagent in the interesterification reaction is that of an amino compound or amino acid or salt thereof. Suitable salts include sodium and potassium salts, especially of the amino acids. The reagent may either be in an anhydrous or hydrated form.
Suitable amino compounds or salts thereof are those selected from the group consisting of alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, proline, aspartic acid, glutamine acid, glycine, serine, threonine, cysteine, tyrosine, asparagines, glutamine, lysine, arginine, histidine, sarcosine, n-methylglucamine, glucamine and taurine. Particularly preferred are glycine, sarcosine, taurine, N-methylglucamine and glucamine.
A second reagent is a fatty acid ester. The term “fatty acid” is herein defined as an 8 to 22 carbon carboxylic radical containing material that may be saturated, unsaturated, branched, unbranched or a combination thereof.
A variety of fatty acid esters may be suitable as co-reactants. Most preferably are the C1-C3 alkyl esters of a C8-C22 fatty acid. Illustrative are methyllaurate, methyloleate, methylinoleate, methylmyristate, methylstearate, methylpalmitate, ethyllaurate, ethyloleate, ethyllinoleate, ethylmyristate, ethylstearate, ethylpalmitate, n-propyllaurate, n-propyloleate, n-propyllinoleate, isopropyllaurate, isopropyloleate, isopropyllinoleate, isopropylmyristate, isopropylstearate, isopropylpalmitate and mixtures thereof. Particularly suitable is methyl cocoate.
The C1-C3 alkyl esters of C8-C22 fatty acids may be generated from triglycerides by hydrolysis with a respective C1-C3 alkanol. Most suitable as the alkanol is methanol. Amongst useful but not exclusive triglycerides are coconut oil, corn oil, palm kernel oil, palm oil, soybean oil, sunflowerseed oil, cottonseed oil, rapeseed oil, canola oil, castor oil and mixtures thereof. Most preferred is coconut oil.
An alternative fatty acid ester suitable as a co-reactant in the process of this invention is the glyceride esters. These glycerides may be selected from monoglycerides, diglycerides, triglycerides and mixtures thereof. Illustrative monoglycerides are monoglyceryl laurate, monoglyceryl oleate, monoglyceryl linoleate, monoglyceryl myristate, monoglyceryl stearate, monoglyceryl palmitate, monoglyceryl cocoate and mixtures thereof. Illustrative diglycerides include glyceryl dilaurate, glyceryl dioleate, glyceryl dilinoleate, glyceryl dimyristate, glyceryl distearate, glyceryl diisostearate, glyceryl dipalmitate, glyceryl cocoate, glyceryl monolaurate monomyristate, glyceryl monolaurate monopalmitate and mixtures thereof. Illustrative but non-limiting triglycerides include oils and fats such as coconut oil, corn oil, palm kernel oil, palm oil, soybean oil, cottonseed oil, rapeseed oil, canola oil, sunflowerseed oil, sesame oil, rice oil, olive oil, tallow, castor oil and mixtures thereof. Most preferred is coconut oil. Use of mono-, di- and tri-glycerides as the co-reactant has an advantage over the C1-C3 alkyl esters of C8-C22 fatty acids. The latter are generally made from breakdown of triglycerides. Conversion from the triglycerides adds an extra step to the process. A disadvantage of using the mono-, di- and tri-glycerides as starting co-reactant is the albeit good but slightly lower yields of resultant acyl amido compound product.
Schematically the process of preparing C8-C22 acyl amido carboxylic or sulphonic acids salts thereof with a C1-C3 alkyl ester of a C8-C22 fatty acid (hereinafter the “monoester route”) corresponds to the following reaction scheme (which optionally includes a triglyceride precursor for illustrative purposes).
wherein R is a C7-C21 saturated or unsaturated alkyl radical; R1 is a C1-C4 alkyl; R2 is hydrogen, CH2COOX or a C1-C5 alkyl radical; R3 is hydrogen; R4 is selected from the group consisting of (CH2)mCO2X, (CH2)mSO3X, CH2NR2(CH2)mOH and glucosyl radicals; R5 is selected from the group consisting of hydrogen, hydroxyphenyl, C1-C6 hydroxyalkyl, C1-C10 alkyl, benzyl, hydroxybenzyl, alkylcarbamido, thioalkyl, and carboxylic radicals; X is selected from hydrogen, metal ions, amine salts and C1-C4 alkyl radicals; and m ranges from 0 to 6.
Schematically the process of preparing C8-C22 acyl amido carboxylic or sulphonic acids or salts thereof directly with a triglyceride as a co-reactant corresponds to the following reaction scheme.
wherein R is a C7-C21 saturated or unsaturated alkyl radical; R″ and R′″ independently are selected from C7-C21 radicals which may be the same or different, hydrogen and mixtures thereof; R2 is hydrogen, CH2COOX or a C1-C5 alkyl radical; R3 is hydrogen; R4 is selected from the group consisting of (CH2)mCO2X, (CH2)mSO3X, CH2NR2(CH2)mOH and glucosyl radicals; R5 is selected from the group consisting of hydrogen, hydroxyphenyl, C1-C6 hydroxyalkyl, C1-C10 alkyl, benzyl, hydroxybenzyl, alkylcarbamido, thioalkyl, and carboxylic radicals; X is selected from hydrogen, metal ions, amine ions and C1-C4 alkyl radicals; and m ranges from 0 to 6.
Salts of the amido carboxylic or sulphonic acid products of the process may have any type of cationic counterion, but preferably are selected from sodium, potassium or mixed cations. Particularly suitable as the R1 group is a methyl radical.
Advantageously, the reaction medium and resultant concentrate may be substantially free of water. By substantially free of water is meant amounts from 0 to 10%, preferably from 0 to 5%, more preferably from 0 to 3%, still more preferably from 0 to 1%, and especially from 0.05 to 1% by weight of water. Water of hydration (such as found associated with the amino carboxylic or sulphonic acid monohydrate) is not considered to count as part of water present in the reaction medium.
The reaction mixture desirably should have a pKa at 25° C. ranging from 9.5 to 13, and preferably from 10.5 to 12.
An advantage of the concentrates as produced by the described process in contrast to the traditional Schotten-Bauman acyl halide route is that unsaturated fatty esters such as oleyl and linoleyl esters can be tolerated and their amides obtained. Normally unsaturated acids will undergo decomposition or generate color bodies in the known processes. Minimum byproducts are produced in the present process to achieve relatively white to no more colored than light tan concentrates. For instance, where glycine is the reactant, we have found no evidence of a glycylglycine or glycyldiketopiperazine. Neither are there any waste streams. As is evidenced from the reaction schematic above, when glycerol is the polyol, the glycerol liberated from the triglyceride can be utilized as a reaction medium. The alcohol (for instance methanol) that distills off from the main reaction can be fed back into the triglyceride hydrolysis reaction to form new methyl fatty acid ester.
Relative molar amounts of amino compound or salt thereof to fatty acid ester as reactants for the interesterification may range from about 3:1 to about 1:3, preferably from about 2:1 to about 1:1, more preferably from 1.3:1 to 1.05:1.
Polyols will serve as a reaction medium. The relative mole ratio of polyol to the amino compound or salt thereof for the reaction may range from about 8:1 to about 1:1, preferably from about 6:1 to about 1:1, and more preferably from about 2:1 to 1:1.
Temperature conditions for the reaction may range from about 50° C. to about 150° C., preferably from about 80° C. to about 140° C., and optimally from about 110° C. to about 130° C.
Basic metal salt containing catalysts may usefully be present to improve reaction speeds and conversion levels. Particularly useful are alkaline and alkaline earth metal containing hydroxides, phosphates, sulphates and oxides including calcium oxide, magnesium oxide, barium oxide, sodium oxide, potassium oxide, calcium hydroxide, magnesium hydroxide, calcium phosphate, magnesium phosphate and mixtures thereof. Most suitable are calcium oxide and magnesium oxide, with the former being preferred. Amounts of the basic metal salt catalyst may range from about 1 to about 20%, preferably from about 1 to about 10%, more preferably from about 1.5 to 5% by weight of starting amino compound present in the reaction.
Buffering compounds may also in some embodiments have utility to improve conversions and reaction times of the present invention. Suitable buffers include trisodium phosphate, disodium hydrogen phosphate, sodium citrate, sodium carbonate, sodium bicarbonate, sodium borate and mixtures thereof. Particularly useful is trisodium phosphate. Amounts of the buffer may range from about 1 to about 30% by weight of the amino compound or salt thereof present in the reaction. Preferably the amount is from about 5% to about 15% by weight of the starting amino compound or salt thereof present in the reaction.
Advantageously, distillation of the alkanol (e.g. methanol) can be done under atmospheric as well as reduced pressure conditions.
Acylamido compounds of the concentrate may be formed of radicals that are saturated, unsaturated or combinations thereof. Unsaturated varieties may exhibit Iodine Number Values ranging from 0.5 to 20, preferably from 1 to 10, optimally from 2 to 8.
Without any further purification, the reaction mass produces a concentrate whose components need not be separated but have been found commercially useful as a combination. Polyol and fatty acid in combination with the main product, C8-C22 acyl amido compounds, may as a concentrate be formulated directly into personal care products such as body washes, toilet bars, shampoos or even lotions.
Colored byproducts ordinarily generated in previously known routes to acyl amido carboxylic or sulphonic salts are avoided through the present process. Confirmation of the absence of colored species, for instance where glycine is a reactant, any glycylglycine and glycyldiketopiperazine has been established as not present through chromatography and/or mass spectroscopy analytical procedures. Yet, perhaps the best indicator of the clean nature of products formed in the process is the visual lack of dark coloration (e.g. absence of tan, brown, or even green/blue heretofore evident from other glycinate forming pathways). Subsequent to the heating step (ii), the hot liquid mass of reaction product bearing acyl amido carboxylic or sulphonic acid/salt product and polyol is removed from the reactor and forms a semi-solid. Color of this mass is evaluated by the Hunter Lab Color Scale. The mass which is a surfactant concentrate from the reaction can vary in color from white to slightly off-white. On the Hunter scale, the key parameter will be the L value which is a reflectance measure of brightness. L should range between 70 and 100, preferably from 75 to 100, optimally 90 to 100. Desirably, the b value can also be considered. The “b” may range from 0 to 20, preferably from 0 to 15, optimally from 0 to 3. Of less impact is the “a” value, which may range from −2 to 8, preferably −1 to 5, and optimally from 0 to 4. Values for the present invention were established by comparing the concentrate color (at the end of the process) with a Color Metric Converter available online at
http://www.colorpro.com/info/tools/convert.htm.
All documents referred to herein, including all patents, patent applications, and printed publications, are hereby incorporated by reference in their entirety in this disclosure.
The term “comprising” is meant not to be limiting to any subsequently stated elements but rather to encompass non-specified elements of major or minor functional importance. In other words the listed steps, elements or options need not be exhaustive. Whenever the words “including” or “having” are used, these terms are meant to be equivalent to “comprising” as defined above.
Except in the operating and comparative examples, or where otherwise explicitly indicated, all numbers in this description indicating amounts of material ought to be understood as modified by the word “about”.
It should be noted that in specifying any range of concentration or amount, any particular upper concentration can be associated with any particular lower concentration or amount.
The following examples will more fully illustrate the embodiments of this invention. All parts, percentages and proportions referred to herein and in the appended claims are by weight unless otherwise illustrated.
Concentrates of sodium cocoylglycinate, as the surfactant component, were prepared by the following procedure. A 250 ml 3-neck glass reactor vessel was used to conduct a series of comparative experiments. A central neck was fitted with a stirring rod with Teflon® blade at one end and a motor for rotating the rod at a second end. A second neck of the reactor was fitted with a water-cooled condenser leading to a Dean-Stark trap for collecting methanol generated in the interesterification reaction. The third neck was fitted with a thermometer attached to a temperature control device. The reactor was externally heated in a glas-col heating mantle. In experiment 1, the reactor was charged with 25 g glycerol, 0.41 g calcium oxide, 17.5 g sodium glycine, and 39 g cocoyl methyl ester. Initially two phases were present in the reactor. The reactants were then heated at 120° C. for 2 hours under constant stirring and dry nitrogen. The reactor contents were then cooled to a point just above solidification and removed from the reactor. The resultant mass constituting the concentrate was a white colored paste. Analysis by liquid chromatography revealed an approximately 87% yield (based on starting glycine) of sodium cocoyl glycinate.
The concentrate contained 50.3% sodium cocoyl glycinate, 7.2% C8-C18 fatty acids, 34.1% glycerol, 1.6% glycine, less than 1.0% methyl cocoate, and the remainder calcium oxide and other minor materials.
Via liquid chromatography/mass spec analysis, the sodium cocoyl glycinate was shown to contain the following fatty acid chain length distribution based on % amounts in the total concentrate: 5.0% C8, 3.8% C10, 27.4% C12, 9.7% C14, 4.5% C16 and 6.9% C18. The C18 glycinate was a mixture of stearic, oleic and linoleic isomers. The unsaturated C18 compounds survived the reaction conditions in contrast to their absence under conditions of the alternate acyl chloride route.
A series of further experiments were conducted to evaluate the importance of pKa (reflective of catalyst and buffer), reaction times and temperatures. These experiments are recorded in Table I. Reactants and conditions are identical to experiment 1, except where otherwise indicated through footnotes for Table I.
1Trisodium phosphate at 1.5 g.;
2Doubled CaO to 0.82 g.;
3Magnesium oxide substitute for calcium oxide at 0.41 g.
4Zinc oxide replacement for calcium oxide at 0.41 g.;
5Propylene glycol replaced glycerol at 25 g.;
6Trisodium phosphate doubled to 3.0 g.
Experiment 5 demonstrates that in the absence of glycerol, hardly any sodium cocoyl glycinate is formed. Similar results are seen in experiments 6 and 7 where only catalyst is present to influence the reaction. From these experiments it is clear that the polyol medium is the crucial aspect in driving good yields.
Experiments 13-15 demonstrate that reactions run at a pKa lower than 9.5 do not result in any glycinate product. Zero yields were noted at pKa of 7.6, 7.7 and 8.9.
A series of experiments were conducted to evaluate concentrate formation in reaction mediums other than polyols. The experiments were run with reactants and conditions identical to experiment 1, except where otherwise indicated as footnotes to Table II.
7Amount of the medium was 100 g.
8Doubled CaO to 0.82 g.
9Trisodium phosphate doubled to 3.0 g.
Based on the results reported in Table II, it is evident that methanol, ethanol, isopropyl alcohol, toluene, isoamyl alcohol and water were ineffective in providing any reasonable yields of sodium cocoyl glycinate. Only polyols such as glycerol and propylene glycol were effective at driving the reactions to high yields and thereby forming the surfactant concentrates of this invention.
A set of experiments were conducted to evaluate whether amino acids other then glycine such as amino sulphonic acids and glucosyl amines would also be reactive in the process and form surfactant functional concentrates. The experiments were conducted with reactants and under conditions identical to experiment 1, except glycine was replaced by sarcosine, taurine, or N-methylglucamine.
1Trisodium phosphate at 1.5 g.
Experiments 22 and 23 produced respectively good yields of sodium cocoylsarcosinate and sodium cocoyltaurate and their concentrates. Amides of N-methyl glucamine were also provided in good yields as detailed in Experiment 24.
A 250 ml 3-neck glass reactor vessel was used to conduct a series of comparative experiments. A central neck was fitted with a stirring rod with Teflon® blade at one end and a motor for rotating the rod at a second end. A second neck of the reactor was fitted with a water-cooled condenser leading to a Dean-Stark trap for collecting distillates generated in the interesterification reaction. The third neck was fitted with a thermometer attached to a temperature control device. The reactor was externally heated in a glas-col heating mantle. In experiment 1, the reactor was charged with 25 g glycerol, 17.5 g Na glycine, 0.41 g calcium oxide, 3 g sodium phosphate (buffer), and 41.2 g coconut oil. Initially two phases were present in the reactor. The reactants were then heated at 130° C. for 2 hours under constant stirring. The reactor contents were then cooled to a point just above solidification and removed from the reactor. The resultant mass was a white colored paste.
Analysis by liquid chromatography revealed an approximately 92.7% yield (based on starting glycine) of sodium cocoyl glycinate. This experiment is identified as number 25 in Table IV. Experiments 26-28 were done with reactants and under conditions identical to experiment 25, except where otherwise noted in the Table.
Typical formulations wherein the concentrate can be utilized are reported under Table V.
1Concentrate from Experiment No. 1.
Formulas Nos. 1 through 6 will exhibit good foaming properties. All the formulas are colored white or relatively colorless.
While the invention has been described in detail with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
This application is a continuation-in-part of Ser. No. 13/192,492 filed Jul. 28, 2011.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3836551 | Schroeder et al. | Sep 1974 | A |
| 4328131 | Carson et al. | May 1982 | A |
| 4812253 | Small et al. | Mar 1989 | A |
| 5154849 | Visscher et al. | Oct 1992 | A |
| 5194639 | Connor | Mar 1993 | A |
| 5300249 | Schwartz et al. | Apr 1994 | A |
| 5529712 | Sano | Jun 1996 | A |
| 5646318 | Dery | Jul 1997 | A |
| 5705462 | Hormes et al. | Jan 1998 | A |
| 5710295 | Woodbury et al. | Jan 1998 | A |
| 5723673 | Kao | Mar 1998 | A |
| 5767059 | Umemoto et al. | Jun 1998 | A |
| 6395692 | Jaworski et al. | May 2002 | B1 |
| 6703517 | Hattori et al. | Mar 2004 | B2 |
| 6958085 | Parrish | Oct 2005 | B1 |
| 7439388 | Harichian et al. | Oct 2008 | B2 |
| 20010034311 | Saxena et al. | Oct 2001 | A1 |
| 20020028954 | Khoury | Mar 2002 | A1 |
| 20040063980 | Raths | Apr 2004 | A1 |
| 20050176615 | Kinoshita | Aug 2005 | A1 |
| 20060090644 | Sirkar | May 2006 | A1 |
| 20060239952 | Hattori | Oct 2006 | A1 |
| 20100029528 | Giles et al. | Feb 2010 | A1 |
| 20130029899 | Hermanson et al. | Jan 2013 | A1 |
| Number | Date | Country |
|---|---|---|
| 2004099 | Jan 1970 | DE |
| 4408957 | Mar 1994 | DE |
| 1801194 | Jun 2007 | EP |
| 1337782 | Nov 1973 | GB |
| 5758653 | Sep 1980 | JP |
| WO2008019807 | Feb 2008 | WO |
| Entry |
|---|
| Co-Pending Appln. U.S. Appl. No. 13/192,490, filed Jul. 28, 2011; titled: “Method for Preparing Fatty Acyl Amido Carboxylic Acid Based Surfactants”. |
| Co-Pending U.S. Appl. No. 13/192,490, filed Jul. 28, 2011; titled General Method for Preparing Fatty Acyl Amido Based Surfactants. |
| Co-Pending U.S. Appl. No. 61/512,434, filed Jul. 28, 2011; titled “Concentrated Fatty Acyl Amido Surfactant Compositions”. |
| Co-Pending U.S. Appl. No. 13/343,726, filed Jan. 5, 2012; titled “Method for Preparing Fatty Acyl Amido Carboxylic Acid Based Surfactant”. |
| Co-Pending U.S. Appl. No. 13/343,728, filed Jan. 5, 2012; titled “Amino Acid Salt Containing Compositions”. |
| Co-Pending U.S. Appl. No. 13/343,727, filed Jan. 5, 2012; titled “General Method for Preparing Fatty Acyl Amido Based Surfactants”. |
| Co-Pending U.S. Appl. No. 13/343,731, filed Jan. 5, 2012; titled “Concentrated Fatty Acyl Amido Surfactant Compositions”. |
| Chen et al., Vinyl Carboxylate an Acylating Reagent for Selective Acylation or Aminea and Dlols, Tetrahedron Letters, 1994, vol. 35 No. 21, pp. 3583-3584. |
| Falk et al., The Preparation and Propertie of Surface-Active N-Acylamino-Methanesulfonates, Journal of America Oil Chem Society, Apr. 1958, vol. 35 No. 4, pp. 171-176. |
| Martin et al., Application of AlMe3-Mediated Amidation Reaction to Solution Phase Peptide Synthesis , Tetrahedron Letters, 1998, vol. 39, 1517-1520, (Jan. 1998). |
| PCT International Search Report in PCT application PCT/EP2012/064772 dated Dec. 11, 2012 with Written Opinion. |
| PCT International Search Report in PCT application PCT/EP2012/064769 dated Dec. 7, 2012 with Written Opinion. |
| PCT International Search Report in PCT application PCT/EP2012/064771 dated Dec. 10, 2012 with Written Opinion. |
| PCT International Search Report in PCT application PCT/EP2012/064770 dated Dec. 10, 2012 with Written Opinion. |
| PCT International Search Report in PCT application PCT/EP2012/064768 dated Nov. 7, 2012 with Written Opinion. |
| Number | Date | Country | |
|---|---|---|---|
| 20130030200 A1 | Jan 2013 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13192492 | Jul 2011 | US |
| Child | 13343730 | US |
