EP1309405B1 - Method for carrying out a chemical reaction - Google Patents

Abstract

Eight containers (1) containing substances (602, 702) are held in holes (71) in a support (70). The eight containers (1) containing different substances or the same substances in different amounts graduated in mole equivalents form a set (69) of containers containing substances, which set can be used for carrying out a chemical reaction.

Description

The present invention relates to a method for carrying out a chemical reaction between at least a first substance and a second substance, in which a pre-dosed amount of the first substance and a pre-dosed amount of the first substance molar equivalent or molar equivalents graded predosed amount of the second substance be placed on a set of substances containing containers as well as on an airtight container containing a pre-dosed amount of a substance.

In chemical and other research and development, in which, at the molecular level, a change in the properties of a substance is made, in particular the chemical industry, the life science industry, universities and other institutions, it becomes more and more important, as fast as possible, safe and sound cost-effective a large number of potential drugs, materials or more generally expressed chemical substances or substance mixtures with marketable properties or reactions or reaction sequences, which lead to already known substances having such properties to find. These are then tested or analyzed. Part of the chemical research nowadays relates to combinatorial chemistry, parallel synthesis, high-speed chemistry and parallel process optimization. Of central importance here is the ability to use known or new chemical reaction types with the least possible adjustments as widely as possible or to optimize a process with respect to its reaction conditions or starting materials can.

Thus, a variety of devices and methods have been provided for carrying out a variety of chemical, biochemical or physical processes in parallel. It has been found that the more the efficiency and automation progresses in performing chemical, biochemical or physical processes, the bottleneck has been shifted to the logistical side, i. to prepare the reactions before they can be started.

Also in the classical, i. usually single or purely sequential chemical synthesis, there is a growing demand that synthesis work such as e.g. Ordering, storage, weighing or dosing, etc. of the necessary chemical synthesis for the corresponding chemical compounds, complexes, mixtures, etc., hereinafter called substances, are improved so that they handled faster or more generally economically and ecologically more efficient In particular, the storage of the substances can be reduced and made more efficient and the percentage of mostly large waste resulting from the fact that often only partial quantities of the ordered quantity are needed can be reduced.

Chemical and biochemical reactions are usually carried out such that a certain number of a first atom resp. Molecule resp. Complex etc. (usually expressed in mol) with a mostly determined number of a second atom, molecule, complex, etc., and possibly further usually specific numbers of atoms, molecules, complexes, etc. spatially brought together under more or less precisely defined conditions in that the different atoms resp. Molecules resp. Complex etc. react with each other. In the organic and inorganic Chemistry, the reactions are often carried out in a solvent.

The result of a chemical reaction is hereinafter abbreviated as a product, the starting materials are referred to as substances. By substances are meant also those which only indirectly or not at all or only potentially influence the stoichiometry of the product to be formed and are supplied for some other reason, e.g. Solvents, catalysts, activators, inhibitors, etc. The conditions under which the substances are combined until the desired product is formed are referred to as reaction conditions.

The ratio of the substances to each other with respect to the smallest chemical unit (atom, molecule, complex, etc.) of the substances is referred to as the molecular ratio or, if the macroscopic term is used, as the molar ratio of the substances. In most chemical reactions, this ratio is more or less decisive, or at least it is important for the experimenter to know this ratio more or less precisely. The ratio of substances among each other is in research and development usually more important than the respective absolute quantities, at least in a certain range, such as a factor of 2.

Since the number of atoms, molecules, complexes, etc. can not be counted economically with the technical equipment available today, the ratios of the substances are usually determined by their weight or volume with the aid of atomic or molecular weight. This implies that the experimenter, who may be both an individual and a robot or an automatic or semi-automatic system, prior to each experiment, first determines the ratios of starting materials he desires. Then decide in which absolute magnitude he carries out the corresponding experiment, which in a certain range is in most cases not absolutely decisive. In the next step he calculates the atomic or molecular weight (in the case of mixtures over the mean value, etc.) the macroscopic size to be measured, ie the weight or the density of the volume. He then weighs the educts or separates the determined volume, for example, from a storage vessel and brings together the reactants under the reaction conditions determined by him.

This process is very time-consuming, time-consuming and, above all, in the implementation of many reactions associated with many potential sources of error. Furthermore, in the chemical research and development of a particular substance usually the smallest possible amount above the amount to be used, usually in a gravimetric or volumetric unit bottled in a container, ordered. Of this amount, often only a fraction is used for the planned experiment. The remainder is then usually stored for later experiments, whereby the container can often no longer be optimally closed optimally. As a result, sometimes unpleasant and / or harmful health vapors are released in the storage rooms. Furthermore, this storage of a variety of, often thousands of compounds is generally a security risk. In many cases, the substances must be disposed of at any time or ideally returned to the manufacturer. This not only causes costs, but also other risks and often environmental problems as a consequence of disposal.

A disadvantage of the previous approach is also that the substances are usually handled open and very volatile, very sensitive or very toxic substances a whole series of safety and Precautions must be taken. In the absence or inadequate presence of such measures, even the quality of the substances may suffer, which may undesirably influence or even fail the experiment. This can also be the case with repeated opening of a container, substance removal and re-closing of the container, since the risk of contamination exists.

Today, the approximately 20,000 fine chemicals most frequently used in chemical and biochemical research and development are usually sold in kilograms, grams, milligrams, micrograms, liters, milliliters or microliters in a wide variety of containers. This has the disadvantage that for each reaction or group of reactions to be carried out after the calculation of the molar ratios and the conversion into the gravimetric or volumetric unit, a corresponding amount must be weighed or measured manually or with special equipment. Even if this is done with automatic equipment or equipment, this process is a tedious and tedious task that involves the problems described above. In addition, since the chemical compounds are present in all possible states of aggregation, different dosing systems must be used. This is not only very cost-intensive, but in many cases, especially with regard to automation, a not yet optimally solved problem, especially taking into account the diversity of only the aggregate states, but also other factors such. the safety requirements or quality maintenance. In addition, the determination of the state of aggregation of a substance by the experimenter usually has to be carried out.

For example, from WO 98/10866 or WO 96/28248 it is known to use containers with a predosed amount of a substance in certain biochemical reactions. However, the various reaction substances used are not coordinated with each other in terms of molar mass, since it is not important in these special reactions. In addition, the substance containers are in particular not suitable for carrying out any chemical reactions.

In view of the disadvantages of the hitherto known methods for carrying out chemical reactions and substances containing containers described above, the invention has the following object. To provide a method and a set of substances containing containers, which allow an economic and / or ecological and / or security risks more efficient implementation of chemical reactions or the preparation thereof. In particular, the preparation of the reaction involving ordering, storage, weighing or dosing, etc. of the substances necessary for the respective chemical reaction should be improved so that they can be handled faster and with less risk. Preferably, the method and the kit should be usable in the widest possible range.

This object is achieved by the inventive method, as defined in independent claim 1, and the inventive set of substances containing containers, as defined in independent claim 18, solved. Claim 36 relates to a use of a set of substances containing containers. Preferred embodiments will become apparent from the dependent claims.

The essence of the invention with respect to the method is that in a method for carrying out a chemical A reaction between at least a first substance and a second substance, in which a predosed amount of the first substance and a pre-dosed quantity of the first substance molar equivalent or with respect to molar equivalents graded predosed amount of the second substance are used, a first predosed amount of the first substance in a first hermetically sealed container and a first pre-dosed quantity of the first substance molar equivalent or molar equivalents second pre-dosed amount of the first substance in a second hermetically sealed container, are released from these substantially completely and are used in the reaction substantially completely.

With the method according to the invention, the at least one substance, which as a rule but not necessarily already pre-dosed by the manufacturer has been airtightly packed into the container, is generally released shortly before the addition into the reaction space or only in the reaction space itself and in the Reaction essentially completely used. This means that substantially all of the pre-dosed amount is brought to the site of the reaction. Thanks to the pre-dosed quantity, the user can do without the time-consuming weighing or measuring of the substance. Thus, even the substance itself is subject to minimal handling by the user outside the reaction space, ie the space in which the substance is reacted, whereby contact with the environment of the reaction space, which as a rule contains atmospheric oxygen and water vapor, to a minimum is limited, which in turn reduces the risk of oxidation or hydrolysis to a minimum, especially in oxygen and water-sensitive substances. As a result, the user is more likely to use this than with a classical addition, ie through prior weighing, measuring, transferring, etc., exactly the substance in exactly the purity as he planned it. Since the invention further unifies logistics, more investment can be made in equipment and devices which operate more accurately and under better controlled conditions than if the preparatory work is performed individually by the user himself before each implementation. Thus, the purities of the substances, the absolute amounts and the molar ratios of the substances among each other become much more precise, which in turn usually makes the experiments more meaningful.

Since the containers each contain a predosed amount of a substance which is essentially completely released and subsequently reacted, the vessel is not opened and closed again, as in the classical method, in which a certain amount is generally removed from a larger vessel. but each container is filled, hermetically sealed and not open until the implementation of the substance. This ensures to a far greater extent that exactly the substance that is planned to be implemented is implemented. In addition, the often dangerous, costly and, because of the user often no longer absolutely hermetically sealed containers, odors spreading storage is considerably reduced.

In addition, only a relatively small fraction of large containers whose substance quantities are usually significantly above the amounts converted in chemical research and development in a chemical reaction are often removed. The remainder must be disposed of frequently because the same substance is no longer needed within a useful period. In the predosed according to the invention Containers eliminates the problem that excess substance must be disposed of.

In addition, the danger potential during transport and storage is reduced by the usually smaller amounts of substance in the pre-dosed containers. In addition, the cost to the user is usually lower because he can order exactly the amount of substance that he wants to release and implement in a planned chemical reaction, especially if, as is often the case, only a fraction plans to use the minimum order quantities of conventional containers.

It should also be borne in mind that the substances used have a wide variety of macroscopic forms, e.g. Aggregate states, grain sizes, densities and viscosities, and there are also chemicals, which are e.g. have difficult-to-handle aggregate states in space conditions, e.g. Waxes, substances with a melting point between 10 ° C and 30 ° C, gases and semi-crystalline substances. The pre-dosed containers allow to neutralize these differences, i. for the user (researcher, robot, automaton, etc.) for handling as far as possible irrelevant.

Viewed from a different perspective, the method according to the invention enables the fine chemical supplier to bring the value-added chain closer to the application without having to hurt critical user taboos in order to be able to offer the user a sustainable and valuable service.

Finally, it must be emphasized that while it is desirable to make available as many commercially available chemicals used in chemical research and development in pre-dosed containers. This but is not necessarily necessary and the invention works independently. The classic method of dosing fine chemicals can be complementary.

Advantageously, in the container, any space not filled with substance is substantially completely filled with a gas, a mixture of gases or a liquid containing less than 5%, preferably less than 1%, preferably less than 0.1%. Contains O ₂ . This has the advantage that, in particular, certain substances can not be oxidized and, if the container is introduced, for example, unopened, for example, into a reaction vessel, the O ₂ does not influence the reaction, in particular also does not oxidize certain other substances.

Advantageously, in at least one of the containers, the non-substance-filled space is substantially completely filled with an inert gas, preferably N ₂ , SF 6, a chlorofluorohydrocarbon or a noble gas, in particular Ar, Ne, Xe or He. Since, if you do not want to fill the container in the production intentionally with an inert gas, the space mentioned is usually filled with air and contains air in relevant amounts of O ₂ , the above advantages apply. But since there are other potentially reactive gases, the inert gas atmosphere is the ideal case, which does not significantly affect both the substance and possibly the reaction mixture.

Advantageously, the essentially completely liberated substance which is essentially completely used in the reaction is at least partially reacted with the at least one further substance. In particular, those substances which are partially reacted are reactive substances and consequently, for example, susceptible to oxidation or hydrolysis and are therefore preferably already pre-dosed and packaged as described (airtight and under inert gas) in the container, so that the user must perform as few actions as possible, such as weighing.

In a preferred embodiment, the substance is a catalyst, inhibitor, starter or an accelerator. In particular, the substances mentioned are used in chemical reactions in relatively small to very small amounts. Accordingly, the above advantages are even more pronounced with certain such substances.

Advantageously, the process according to the invention is characterized in that the container is dense to organic solvents, preferably generally to organic compounds. Advantageously, the container is sealed to inorganic solvents, preferably generally to inorganic compounds. In this case, "dense" is to be understood that the organic compound, the vessel wall is not essential (scale is glass with a vessel wall thickness of 0.005 mm) can penetrate without destroying them. This has the advantage that if the container comes into contact with organic or inorganic compounds (before or after the addition of the container into the reaction space, ie also during storage), the substance contained therein can not be dissolved or reacted. This ensures both the quality of the substance and the safety until the container is used, ie until the container is opened.

Advantageously, at least one, preferably at least two, of the substances is a pure chemical compound. In the majority of chemical reactions in the chemical Research and development use pure chemical compounds. Precisely because the substances are enclosed airtight in the containers and are released only before the reaction with other substances, the use of such containers for pure chemical compounds makes sense to ensure the purity to a great extent.

Advantageously, at least one of the substances is a pure chemical compound in solution or suspension. Substances offered by the fine chemical suppliers for chemical research and development in solutions or suspensions are often offered in such as they are very sensitive to contact with the environment, e.g. against hydrolysis, oxidation, etc. are. Especially for such substances, the hermetically sealed containers offer optimal conditions, since the substance is released with minimal handling only shortly before the implementation or even during this.

In a preferred embodiment, the chemical reaction is carried out in a, preferably organic, solvent or solvent mixture. The substances are usually released shortly before the addition of a solvent or even in this self from the container. In the solvent, they are in turn protected against, for example, oxidation with atmospheric oxygen or hydrolysis by atmospheric moisture. Thus, use of containers according to the invention makes sense, especially in solvent chemistry, especially since very sensitive chemical reactions are often carried out in solvents.

Advantageously, the process according to the invention involves a further substance which has no stoichiometric influence on the product resulting from the chemical reaction, preferably a catalyst, solvent, activator or inhibitor. Especially in reactions in which catalysts, activators, inhibitors, etc. are involved, it is often necessary that highly pure chemical compounds are used; so as not to disturb the course, e.g. Do not "poison" the catalyst, inhibitor or activator.

In an advantageous embodiment, the reaction is an organic chemical reaction. Most of the reactions carried out in chemical research and development are organic chemical reactions, which is why there is a great need for rationalization in this area. This is also shown by the most widely used parallel synthesis methods in this field.

Preferably, the method is characterized in that at least one of the substances is an organometallic compound. Since just organometallic compounds are usually very sensitive to oxidation (eg by atmospheric oxygen) and hydrolysis, it is particularly useful to use this class of compounds pre-dosed and airtight in containers, so that the handling outside the reaction chamber can be reduced to an absolute minimum and so the quality or the content of the pure organometallic compound is not impaired.

Preferably, the chemical reaction takes place in a reaction vessel, wherein preferably the reaction conditions under which the substances are reacted with each other be different from the conditions outside the reaction vessel. Especially when the reaction is carried out in a reaction vessel, very specific and controlled conditions are often sought. At the same time, the aim should also be that the substance should not be exposed to the conditions outside the reaction vessel, if possible at all, or at least only a little. By using a predosed substance in an airtight container, which is opened just before the addition to the reaction vessel or only in this itself, this can be achieved with relatively little effort.

In a preferred embodiment, at least two, preferably a plurality of reactions are carried out in parallel, in which in each case at least one hermetically sealed container, each containing a pre-dosed amount of a substance which is released from this, is used. In parallel synthesis or combinatorial chemistry, it is desired that a user can perform more reactions per unit of time. The use of pre-dosed containers can eliminate the time-consuming metering by the user, often even under difficult to control conditions and high concentration. The user inserts e.g. the reactor simply to a pre-dosed in a container substance.

Advantageously, the reactions differ at least at one point, either in the reaction conditions or one of the substances used, in particular the amount thereof. Especially if the substances used or their amounts vary in reactions carried out in parallel, for example, the user becomes highly concentrated and a extremely time-consuming calculation, time-consuming weighing or metering, often under special conditions, requires what is largely eliminated by adding a pre-dosed in a container substance.

Preferably, at least two of the substances are in each case in at least one hermetically sealed container, each containing a predosed amount of a substance before, and are released from this substantially completely and used in the reaction. Most of the above-mentioned advantages weigh twice when two substances pre-dosed in containers are used; moreover, with a corresponding predosing, the time-consuming calculation of the ratios of the molar equivalents is omitted or at least greatly simplified.

Advantageously, the substances in the container (s) have a molecular weight of less than 10,000, preferably less than 5,000, more preferably less than 1,000. Most substances sensitive to atmospheric oxygen or water vapor have relatively small molecular weights. For this reason, it is particularly advantageous to add them to the reaction in containers which release the substances only shortly before the reaction or first in the reaction mixture.

Advantageously, the process is a chemical or biochemical synthesis process, preferably for the preparation of a product or product mixture to be investigated. In particular, chemical, to a lesser extent biochemical processes are sensitive to impurities, which arise, for example, by oxidation or hydrolysis of substances, which of a handling of the same outside the reaction space. As a result, the measurement results, analyzes or general examinations of the product resulting from the substances can be influenced. The use of pre-dosed substances in containers, which release them only shortly before they are added to the reaction space or even into the reaction space, often reduces the risk of influencing the results.

In an advantageous embodiment variant, at least one of the substances is released by at least partial, preferably irreversible, cancellation of the airtight sealing of the container in a reaction vessel. The release in the reaction vessel has the advantage that the substance is not contaminated during the feed. The irreversible cancellation of the airtight sealing the container prevents the container is closed again.

Advantageously, at least one of the substances is released by at least partial, preferably irreversible, cancellation of the airtight sealing of the container directly where the reaction takes place. The fact that the substance is released only where the reaction takes place, the risk of a change in the substance, e.g. with respect to oxidation by atmospheric oxygen, hydrolysis by water vapor, etc., before it enters the reaction, greatly reduced.

In another advantageous embodiment variant, at least one of the substances is replaced by at least partial, preferably irreversible, cancellation of the airtight sealing released the container and then added to the at least one other substance.

Preferably, the at least partial cancellation of the airtight sealing of the container takes place by untargeted application of a chemical, physical or mechanical action. If the containers are suitable, e.g. a container are fed to a reaction mixture and at most later, ie during the reaction or individual containers at certain times of the reaction, by e.g. the action of a rotating magnetic stirrer, ultrasound, a solvent, an explosive device of some kind, etc. e.g. irreversibly destroyed and subsequently release the substance. Thus, not only the advantages described above are achieved, but the reaction can also be controlled specifically. This is a sensible external control particularly in reactions which do not or only with difficulty permit addition after the start of the reaction, e.g. if the reaction takes place in an airtight sealed container, possibly under pressure, in the parallel execution of many reaction in which can no longer be parallel and simultaneously metered, etc.

In an advantageous embodiment variant, the at least partial cancellation of the airtight sealing of the container takes place by opening the container at a designated container location, in particular by separating at a predetermined separation point. In the presence of a predetermined breaking point, the advantages described above can be used more selectively. In addition, a higher reliability of the opening of the container is usually achieved. Furthermore, the predetermined separation point, in particular with regard to material, be made differently, and possibly can be made as regards material properties for the relatively small amount of another material, which is possibly used for the predetermined breaking point, inasmuch as an optimal, more precisely controllable release of the substance is achieved and at most with respect to non-influencing the chemical Reaction (eg by inert material) are made compromises.

In another advantageous embodiment variant, the opening of the container takes place by means of a tool, with which then preferably present in the container substance of at least one further substance is added. Thus, the pre-dosing of the substance in the container can be combined with the classical method in which the substance without container is fed to the reaction mixture, e.g. a tool opens the container and the substance e.g. expels, leaks, blows out, etc .. This is then advantageous if a certain substance is to be added slowly. If the tool opens the container just prior to addition to the reaction vessel, many of the above-mentioned benefits are retained. If the tool opens the container in the reaction vessel or even in the reaction mixture itself and the container releases the substance there, the above-mentioned advantages remain practically all.

Advantageously, the opening of the container by a piercing of the container, preferably by a two-stage piercing, wherein in a first stage, a container wall portion and in a second stage, an opposite container wall portion are pierced, wherein after the first stage, preferably the container interior, a solvent is supplied. In this way, a substance can even be dosed as a solution in a solvent to obtain most of the above-mentioned advantages, for example, by piercing a container wall part of a robot needle connected to a solvent reservoir, such as in a Gilson ASPEC 233, the corresponding amount Solvent added, possibly repeatedly absorbed for mixing and the solution again discharged into the container and possibly absorbed again and then pierces the opposite container wall part and dosed the solution thus prepared directly into, for example, a reaction vessel. This process can even be carried out directly in the reaction vessel with a corresponding device (manual or automated tool).

In another advantageous embodiment variant, the at least partial cancellation of the airtight sealing of the container takes place by dissolving the container or a part of the container or by detaching a part of the container. In a container with the corresponding properties, in turn, a targeted opening of the container by e.g. a solvent can be achieved outside or inside the reaction vessel.

In yet another advantageous embodiment variant, the at least partial cancellation of the airtight sealing of the container takes place by destruction, preferably breaking, of the container. Above, the opening was described by an undirected physical force. In principle, the same advantages apply to destroying the container. For example, it is possible to precisely determine the time of addition, even if the containers have possibly already been brought into the reaction vessel at an earlier point in time have been. Furthermore, the user can also break a suitable container by hand using gloves directly over the reaction vessel and empty the substance into the reaction vessel. This last variant is simple and opens the possibility to supply the substance without container while preserving many of the advantages described above the reaction mixture.

Advantageously, the at least one container of a material that does not affect the reaction is preferably chemically inert in the reaction, preferably at least partially made of an inorganic material. For obvious reasons, the container should not be chemically attacked by the substance (contamination of the substance, danger to the environment, etc.). Ideally, the container material is inert inside and outside in a very broad chemical spectrum, so that the same container material can be used for as many substances as possible, and thus fewer considerations and tests, both by the manufacturer and the user must be performed. Furthermore, it is at least in some applications advantageous if the container can be fed directly to the reaction mixture and this releases the substance directly there. However, this is only usefully possible if the container material does not affect the reaction, is even better inert. So that the user does not have to make a special consideration for each reaction, the container material is ideally inert to most of the substances used in the chemical synthesis and used reaction mixtures or at least does not significantly affect most reactions.

Preferably, the at least one container is at least partially, preferably substantially entirely, of glass, preferably silicate glass, or a glass-like material. Most reaction vessels used in organic chemistry today are made of glass. Glass is considered to be a very inert material that does not affect the reactions in a wide range. Most users are aware of the opportunities and risks of glass. Besides HF, there are only a few substances and reaction mixtures regularly used in chemical research and development, which are not resistant or at least not influencing glass. Glass also does not dissolve in organic and the vast majority of inorganic solvents, so if the container is e.g. is completely added to the reaction mixture and the substance is thus released directly in the reaction mixture, easily, e.g. by filtration from the reaction solution, can be separated. Furthermore, glass is relatively easily fragile, but under some conditions quite well suited as reasonably stable container. The container wall thickness may e.g. be chosen so that the container can be relatively easily transported in a good further packaging, but can be smashed by a magnetic stirrer in a reaction vessel.

In principle, a wide variety of containers are conceivable in which a chemical substance is completely surrounded by glass.

In an advantageous alternative variant, the at least one container consists at least partially of polymers. For certain substances, such as HF or HBr, are polymers, especially polyethylene, polypropylene and special Applications Polytetrafluoroethylene as container materials most suitable because they have the necessary for such and similar compounds chemical stability.

Advantageously, the at least one container is at least partially made of metal and in particular contains a gaseous substance. Gaseous substances can be placed in such containers even under pressure as a whole in a reaction chamber and sealed airtight. The container may be such that the gas is released into the reaction vessel under certain conditions, e.g. by dissolving a sized seam, releasing a pore-filled second material, etc.

The containers of the invention may be similar to commercially available laboratory disposable containers such as e.g. Test tubes, pipettes, ampoules, syringes, tubes with or without screw cap, etc., be designed, which are modified so that an irreversible cancellation of the airtight sealing is possible.

Advantageously, the predosed amount is 1 nmol to 1 000 mol, preferably 1 nmol to 10 mol, more preferably 1 nmol to 1 mol, even more preferably 1 nmol to 100 mmol, more preferably 1 nmol to 10 mmol. Especially with small batches (small amounts with respect to moles), the advantages mentioned above are particularly important, since the smaller the batch, the more difficult it is to handle the relative accuracy of the metered addition. On the other hand, the vast majority of chemical reactions in chemical research and development are on a scale smaller than 1'000 mol, most in one of less than 10 mol, and especially in chemical research carried out in such a smaller than 1 mol. Furthermore, the containers are particularly efficient in the mentioned areas and in smaller batches, especially because the smaller batches are much more frequent and are often carried out in parallel today.

The predosed amount is preferably 1, 2, 5, 10, 20, 50, 100, 200, 500, 1'000, 2'000, 5'000, 10'000, 20'000, 50'000, 100'000 , 200,000, 500,000, 1,000,000, 2,000,000, 5,000,000, 10,000,000, 20,000, 50,000,000 or 1,000,000 '000 nmol, preferably 1, 2, 5, 10, 20, 50, 100, 200, 500, 1'000, 2'000, 5'000, 10'000, 20'000, 50'000, 100'000 , 200'000, 500'000, 1'000'000, 2'000'000, 5'000'000 or 10'000'000 nmol. Especially the gradations as usual in the monetary systems have proven themselves in terms of simplicity in handling and are therefore familiar to every user. They are easy to calculate in terms of overview and calculation of the molar equivalents.

Advantageously, the predosed amount is 1, 10, 100, 1'000, 10'000, 100'000, 1'000'000 or 1'000'000'000 nmol, preferably 1, 10, 100, 1'000, 10'000, 100'000 or 10'000'000 nmol. A decimal system of graduated containers is particularly easy to handle in terms of clarity. For the sake of simplicity and clarity, it is often accepted that, compared to the system described above, more but not too many containers have to be used in order to achieve the desired accuracy in the corresponding area.

Preferably, at least one first container with a first predosed amount of the first substance, at least a second container having a second predosed amount of the first substance graded with respect to molar equivalents and at least one third container having a predosed amount of molar equivalent or molar equivalents of the second substance pre-metered to the first predosed amount. By using several predosed substances, the advantages discussed above are added.

Advantageously, at least one first container having a first predosed amount of the first substance and at least one second container having a first predosed amount of molar equivalents of the second predosed amount of the first substance are used. Thus, the user can use container sizes so that, in particular if a reasonable gradation (eg as described above in a tens system) is present, can achieve virtually any accuracy and not for each substance for each number of moles in a specific area per a container available which would not only make logistics and manufacturing more difficult, but also a loss of clarity.

With regard to the advantages of the objects of further dependent method claims, reference is made to the following description of the inventive set of substances containing containers.

The essence of the invention with respect to the set of substances containing containers is that this at least one first container with a first predosed amount of a first substance, at least one second container having a first predosed quantity in terms of molar equivalents graduated second predosed amount of first substance, at least one third container having a pre-dosed quantity of the first substance molequivalent pre-dosed amount of a second substance and at least a fourth container having a first predosed amount of the second substance in the third container in terms of molar equivalents of the pre-dosed amount of the second substance.

Thus, the user has a set of substances containing containers available for a particular application, with which he can perform various chemical reactions. This has the advantage that the substances can be added very conveniently to the reaction space by means of containers from which the corresponding substances are normally substantially completely released, possibly together with further substances which are added to the reaction space in the classical manner. Thanks to the pre-dosed quantities of substances, the user can do without the time-consuming weighing or measuring of the substance. Moreover, the substance itself is subject to minimal user handling outside the reaction space, i. the space in which the substance is reacted exposed, whereby the contact with the environment of the reaction space, which usually contains atmospheric oxygen and water vapor, is kept to a minimum, which in turn especially in oxygen and water-sensitive substances, the risk of oxidation or hydrolysis reduced to a minimum, with which the user is more likely than in a classical addition exactly the substance in the purity, which he planned to implement.

The set further has the advantage that not only a substance is predosed in a container, but just a set of predosed in containers arranged substances. With such a set can be different reactions be carried out, for example, using at least a first and at least one third container, which contain two different substances, possibly additionally with classically added substances. Using one or more of the second containers, in which a second quantity of the first substance graduated in terms of molar equivalents to the first pre-dosed quantity is predosed, not only batch sizes corresponding to the first pre-dosed quantity in the first container or a multiple thereof can be realized , but also intermediate sizes.

It is also possible, for example, to realize two reactions in which a first substance from a first container is released in a first reaction and reacted with a further substance, and a second substance from a third container is released in a second reaction and reacted with a further substance in such a way that the two reactions are molar equivalents, which can be achieved by the second predosed substance released from a third container being molar equivalent to the first predosed amount of the first substance in the first container, or at best using a corresponding number of Containers: Especially in parallel synthesis, it is desirable that different approaches be performed equimolar. This provides more clarity, but also the same expected product, which simplifies eg the subsequent dosing, storage, dilution with a solvent under adjustment of a same concentration and the calculations for further reactions, etc. In the chemical development, an equimolar reaction is often desired or even required, since the absolute size of the approach often has a not negligible influence on the reaction parameters, and these are in fact to be investigated in such reactions.

It is also possible, e.g. if the amount of predosed second substance in a third container equals an integer multiple (factor z) of the amount of the first substance in a first container, perform a reaction such that x / z equivalents of the first predosed substance react with one equivalent of the second substance where x is the number of first containers used. Since a second predosed amount of the first substance in turn is present in a second container and this is graded to the first predosed amount of the first substance in the first container, further gradations can be realized with respect to molar equivalents.

In addition, what has been said in connection with the method according to the invention applies, in particular with regard to the explanations relating to claim 1. This also applies to the dependent claims, which are therefore only partially discussed explicitly for this reason.

Advantageously, the set of containers containing substances is so composed that the predosed amount of the second substance in the third container is molar equivalent to the first predosed amount of the first substance in the first container. Thus, it is ensured that the user performs a chemical reaction between an amount of the first substance and an amount of the second substance which is molar equivalent to the amount of the first substance or a multiple thereof at a desired molar ratio of the first substance to the second substance of 1: 1, simply use a first container with the first substance and one or more third container with the second substance. At a different desired molar ratio of the first substance to the second substance, the number of containers must be adjusted accordingly.

Advantageously, the predosed amounts of further substances in further containers for predosed amount of the first substance in the first container are each molar equivalent amounts or integral multiples thereof. This allows the user to perform a variety of reactions using the easy-to-use set.

In an advantageous embodiment, at least one of the substances is a pure chemical compound, preferably both substances are pure chemical compounds. Chemical reactions are carried out in most cases with pure compounds as starting substances (so-called educts). If the chemical compound is as pure as possible, the user knows exactly what he is using and can then carry out the reaction relatively independently of the supplier of the corresponding fine chemicals. As a rule, so-called pure chemical compounds are offered in purities of between 90 and 99.999%. Often, different degrees of purity such as e.g. 98% and 99% offered. In practice, both are considered as pure chemical compounds. In addition, there is a particular advantage of pre-dosing in a sealed container in that the manufacturer of such containers can precisely define their contents and control their quality and that the containers preferably release the substance only in the reaction vessel. This ensures that the purity stated by the manufacturer of the substance can not be achieved by handling, e.g. Weighing, the substance outside the reaction vessel suffers. This increases the reproducibility of the reaction.

Advantageously, the set of substances containing containers comprises a plurality of containers with different predosed substances in different amounts, wherein the amounts are each graded with respect to molar equivalents. The set of substances becomes more and more advantageous for the user, the more connections it contains, which the user repeatedly uses. It is expedient, in particular, to have the basic chemical used most frequently and the most delicate and most complicated to be pre-dosed in containers available. An example of this is sodium hydride (NaH), which today is usually offered suspended in an oil, with the result that it often has to be freed of this by washing with hexane before the reaction. Since NaH is also highly sensitive to air, this is a complex, unsafe and labor-intensive work. The suspension in oil is mainly offered so that the NaH at least during handling remains reasonably stable and does not react with the humidity to NaOH. Due to similar handling difficulties, the predosing in a sealed container, for example, even with K ₂ CO ₃ , LiAlH ₄ , Na and CH ₃ CH ₂ COO (COOCH ₂ CH ₃ ) is particularly advantageous.

Preferably, the set of containers containing substances is composed so that the at least one first container x nmol of the first substance and the at least one second container y * x / 1 000 nmol of the first substance, wherein x and y are integers and y is preferably a number from 1'001 to 1'000'000, more preferably from 1'010 to 100'000, even more preferably from 1'100 to 10'000. The vast majority of substances used in chemical research and development have a purity of less than 99.99% by weight. Thus, it makes sense that a level is selected for the substance quantities in the containers, which is substantially above this value for most substances. The grading should not include too big steps and the smallest Predosed amount of substance should be sufficiently small so that for a desired amount of substance preferably less than 1'000, more preferably less than 100, more preferably less than 10, containers must be used and a sufficient accuracy is achieved. The choice of the gradation is an optimization matter, comparable to the choice of a monetary system, to which, however, comes a third dimension, namely that different substances exist.

In a preferred embodiment, y is 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000 or 10,000, preferably 2,000, 5,000 or 10,000, more preferably 5,000 or 10,000. With such a set of substances containing containers, it is ensured that the range of gradation is convenient and thus advantageous for the user. At y = 2,000, the user can dose exactly to the quantity x nmol and must use a maximum of two containers in the range from x nmol to 2y / 1'000 nmol. This is analogous to all values of y listed here, i. at y = 3'000 three containers, at y = 4'000 four containers, etc ..

If, for example, of a substance as described above three containers are used with different amounts of substance, it is advantageous that the y between the first and second and that between the second and third container are not the same size, so intermediate sizes can be introduced and the same Dosing accuracy fewer containers must be used. This in turn can increase the user friendliness considerably. Especially the gradation of a substance of x nmol, 2x nmol, 5x nmol and 10x nmol is particularly advantageous and is eg also at a usual monetary system in the decimal system so handled. The grading of a substance of x nmol, 5x nmol and 10x nmol in turn has the advantage that the user must handle fewer container sizes and yet not too many containers in the mentioned range. At a Y of 10'000, the user can still dose exactly to the amount of x nmol and has to use a maximum of 10 containers in the range from x nmol to 2y / 1'000 nmol, although at most a little more containers in total even fewer container sizes must handle.

Advantageously, x is a number from 1 to 1,000,000,000,000, preferably 1 to 10,000,000,000, more preferably 1 to 1,000,000,000, even more preferably 1 to 100,000. 000, more preferably 1 to 10'000'000. These numbers result from the fact that the set according to the invention of containers containing substances is used in particular in chemical research and development and in this field of application usually in a range of 1 nmol to 1,000,000,000,000 nmol, preferably 1 to 10 More preferably 1,000 to 1,000,000 nmol, more preferably 1 to 1,000,000 nmol, even more preferably 1 to 100,000,000 nmol, even more preferably 1 to 10,000,000 nmol.

The advantage of smaller containers is that they are easier to handle and release of the substance is usually faster, which can prevent concentration effects and other problems. In addition, in the case of several smaller containers, the metered addition of a substance can be graduated in time, which is often required, in particular in chemical synthesis. In addition, for example, catalysts in relatively small amounts, for example 0.001 to 10% of the amount of stoichiometrically used Substances used. Since in the chemical research and in the first phase of the chemical development today predominantly in a range of 1'000 nmol to approximately 1'000'000'000 nmol one works, a catalyst in this lowest range still by addition of a container with a content of 1 nmol to 0.1%. Furthermore, the development in chemical research is to try to reduce the batch size and in the micromolar and even for various reasons, eg use of less chemicals, reduction of the space requirement of the chemical reaction, especially in parallel synthesis or combinatorial chemistry to bring nanomolar range. Especially in the latter area, it is particularly important that the substances are brought into the reaction space in a particularly pure form and are metered in particularly accurately. This is much more possible with the containers according to the invention, since the production of the containers is generally carried out centrally and quality assurance measures and controls can be rationally implemented in the case of a large number of centrally produced containers.

In a preferred embodiment, x is 1, 2, 5, 10, 20, 50, 100, 200, 500, 1'000, 2'000, 5'000, 10'000, 20'000, 50'000, 100 ' 000, 200,000, 500,000, 1,000,000, 2,000,000, 5,000,000, 10,000,000, 20,000,000, 50,000,000 or 1,000 000'000, preferably 1, 2, 5, 10, 20, 50, 100, 200, 500, 1'000, 2'000, 5'000, 10'000, 20'000, 50'000, 100'000 , 200'000, 500'000, 1'000'000, 2'000'000, 5'000'000 or 10'000'000, more preferably 1, 10, 100, 1'000, 10'000, 100 '000, 1'000'000 or 10'000'000, more preferably 1, 10, 100, 1'000, 10'000, 100'000 or 1'000'000. This ensures that the smallest amount of container containing the first substance is a size that is reasonably convenient for the user to handle and that the gradation can correspond to the decimal system for a corresponding y. This simplifies the user's intended thinking in containers or equivalents.

Advantageously, the kit according to the invention has at least three, preferably at least 5, more preferably at least 10, even more preferably at least 100, even more preferably at least 1000 containers with different substances. The more substances the user has available in his molar-equivalent pre-dosed containers for his reactions, the more likely he or she is to be able to perform a specific reaction without having to additionally resort to conventionally added substances.

Preferably, the set to the containers with different substances in each case at least one, preferably at least three, more preferably at least five, further container with the same substance in the first predosed amount of the respective substance in terms of molar equivalents of graded amounts. This ensures that the user has two or more dosages of the substances available in containers. This is advantageous since in many reactions the substances are not used in equimolar amounts and different amounts can be achieved by combining differently filled containers.

Preferably, the containers of the different substances are equally graduated with respect to molar equivalents. So that the user effectively has to think practically only in containers or equivalents and at a certain Number of containers as directly as possible the ratios of the equivalents of the substances with each other and thus only one substance must determine the absolute batch size, it makes sense that not only many substances in containers with some gradations are available, but that the gradations are the same. If this is the case, the user gains an overview and time. In his field of application, the user has the most optimal way to store all substances in containers in such a way that all gradations in terms of container content are the same and he has no restrictions regarding substance selection and accuracy selection, and nevertheless only with containers whose contents are completely contained in the product Reaction is used, can work.

Fig. 1 -

einen Längsschnitt eines Ausführungsbeispiels eines erfindungsgemässen luftdicht verschlossenen Behälters, der eine vordosierte Menge einer Substanz enthält;

Fig. 2 -

einen Längsschnitt des Behälters von Fig. 1, bevor er mit der Substanz gefüllt und luftdicht verschlossen worden ist;

Fig. 3 -

einen Längsschnitt des Behälters von Fig. 2, nachdem die Substanz eingefüllt worden ist;

Fig. 4 -

eine Schnittansicht einer Apparatur zur Durchführung einer chemischen Reaktion mit Hilfe erfindungsgemässer Behälter, die von einem sich drehenden Magnetrührer zerstört werden;

Fig. 5 -

eine Perspektivansicht der Apparatur von Fig. 4;

Fig. 6 -

eine Schnittansicht einer alternativen Apparatur zur Durchführung einer chemischen Reaktion mit Hilfe erfindungsgemässer Behälter, die von einem sich drehenden Magnetrührer zerstört werden;

Fig. 7 -

eine Schnittansicht einer weiteren alternativen Apparatur zur Durchführung einer chemischen Reaktion mit Hilfe erfindungsgemässer Behälter, die mittels einer Nadel zerstört werden;

Fig. 8 -

einen Längsschnitt einer Ausführungsvariante eines erfindungsgemässen Behälters, von dem ein Behälterwandteil mit einer Nadel durchstochen worden ist, die gerade ein Lösungsmittel zuführt;

Fig. 9 -

einen Längsschnitt des Behälters und der Nadel von Fig. 8, wobei die Nadel das Lösungsmittel mit der darin gelösten Substanz aufgesaugt hat;

Fig. 10 -

einen Längsschnitt des Behälters und der Nadel von Fig. 8, wobei die Nadel den dem Einstichort gegenüberliegenden Behälterwandteil durchstochen hat und die Lösung mit der Substanz freigibt;

Fig. 11 -

einen Längsschnitt des Behälters und der Nadel von Fig. 8, wobei als Alternative zu der in Fig. 10 dargestellen Variante die Nadel wieder aus dem Behälter gezogen worden ist und die Lösung mit der Substanz daneben freigibt;

Fig. 12 -

einen Längsschnitt des Behälters und der Nadel von Fig. 8, wobei als Alternative zu den in den Fig. 9-11 dargestellen Varianten die Nadel ohne vorheriges Aufsaugen des Lösungsmittels mit der darin gelösten Substanz den dem Einstichort gegenüberliegenden Behälterwandteil durchstochen hat;

Fig. 13 -

einen Längsschnitt des Behälters und der Nadel von Fig. 12 nach dem Herausziehen der Nadel aus dem Behälter;

Fig. 14 -

einen Längsschnitt einer alternativen Ausführungsvariante eines erfindungsgemässen luftdicht verschlossenen Behälters, der eine vordosierte Menge einer Substanz enthält;

Fig. 15.1

bis 15.4 - die Herstellung von Behälterrohlingen für Behälter gemäss Fig. 14 in verschiedenen Verfahrensschritten;

Fig. 16 -

eine Perspektivansicht eines Teils einer von Hand oder von einem Roboter geführten Apparatur, mit welcher mit einer vordosierten Menge einer Substanz gefüllte Behälter luftdicht abgeschmolzen werden;

Fig. 17 -

eine Perspektivansicht eines Teils einer von Hand oder von einem Roboter geführten alternativen Apparatur, mit welcher mit einer vordosierten Menge einer Substanz gefüllte Behälter unter einer inerten Atmosphäre luftdicht abgeschmolzen werden;

Fig. 18 -

eine Perspektivansicht eines Ausführungsbeispiels eines erfindungsgemässen Sets von 8 Substanzen enthaltenden Behältern, welche in einem Gestell gehaltert sind;

Fig. 19 -

eine Perspektivansicht eines alternativen Ausführungsbeispiels eines erfindungsgemässen Sets von 96 Substanzen enthaltenden Behältern, welche in einem Gestell gehaltert sind;

Fig. 20 -

eine Perspektivansicht einer alternativen Ausführungsvariante eines erfindungsgemässen luftdicht verschlossenen Behälters in der Form eines Quaders;

Fig. 21 -

eine Schnittansicht einer alternativen Ausführungsvariante eines erfindungsgemässen luftdicht verschlossenen Behälters in der Form einer Kugel;

Fig. 22 -

einen Längsschnitt einer alternativen Ausführungsvariante eines erfindungsgemässen luftdicht verschlossenen Behälters in der Form eines Zylinders, welcher in der Mitte eine Sollbruchstelle aufweist;

Fig. 23 -

einen Längsschnitt einer alternativen Ausführungsvariante eines erfindungsgemässen luftdicht verschlossenen Behälters in der Form eines Zylinders, der an der Aussenseite mit einem Strichcode versehen ist;

Fig. 24 -

einen Längsschnitt einer alternativen Ausführungsvariante eines erfindungsgemässen luftdicht verschlossenen Behälters in der Form eines Zylinders, der an der Aussenseite mit einer chemischen Formel versehen ist;

Fig. 25 -

einen Längsschnitt einer alternativen Ausführungsvariante eines erfindungsgemässen luftdicht verschlossenen Behälters in der Form eines Zylinders, welcher in der Mitte zusammengeleimt ist;

Fig. 26 -

einen Längsschnitt einer alternativen Ausführungsvariante eines erfindungsgemässen luftdicht verschlossenen Behälters, der zwei Sollbruchstellen aufweist;

Fig. 27 -

eine Perspektivansicht von 96 Behälterrohlingen, welche in einem Rack gehaltert und mit je einer vordosierten Menge einer Substanz gefüllt sind und mit einer dünnen Glasplatte abgedeckt werden;

Fig. 28 -

das Anschweissen der dünnen Glasplatte an die 96 Behälterrohlinge gemäss Fig. 27 mit Hilfe einer feuerresistenten Platte;

Fig. 28.1 -

einen vergrösserten Ausschnitt aus Fig. 28, der ein ringförmiges Loch in der feuerresistenten Platte zeigt;

Fig. 29 -

eine Perspektivansicht des entsprechend den Fig. 27, 28 und 28.1 erhaltenen Sets oder Kits von 96 Substanzen enthaltenden Behältern;

Fig. 30 -

eine Perspektivansicht eines alternativen Ausführungsbeispiels eines erfindungsgemässen Sets oder Kits von 96 Substanzen enthaltenden Behältern mit einer oberen und einer unteren dünnen Glasplatte;

Fig. 31 -

eine Perspektivansicht eines alternativen Ausführungsbeispiels eines erfindungsgemässen Behälters, welcher durch Anschweissen eines dünnen Deckels verschlossen werden soll;

Fig. 32 -

einen Längsschnitt des Behälters von Fig. 31 im verschlossenen Zustand;

Fig. 33 -

einen Längsschnitt des verschlossenen Behälters von Fig. 32, welcher mit einer Nadel durchstochen worden ist, welche Lösungsmittel zum Lösen der Substanz zugibt;

Fig. 34 -

eine Perspektivansicht einer Apparatur nach Fig. 4, wobei hier in der Reaktionslösung ein noch nicht zerstörter Behälter, der eine vordosierte Menge einer Substanz enthält, zu sehen ist.

Fig. 35 -

eine schematische Perspektivansicht einer Apparatur von parallelen Reaktoren, welchen ein Set von Behältern mit vordosierten Substanzen parallel zugegeben wird;

Fig. 36 -

einen hohlen Glasstab, welcher zur Herstellung eines Rohlings dient;

Fig. 37 -

einen hohlen Rohling zur Herstellung eines Behälters mit sehr dünner Wandung;

Fig. 38 -

einen hohlen Glasstab, welcher an einer Stelle auf einer Länge von ca. 15 cm zu einem sehr dünnen Glasstab ausgezogen ist;

Fig. 39 -

den hohlen Glasstab von Fig. 38, bei welchem derjenige Teil ausgeschnitten ist, der eine dünne Wandung und einen gewünschten Aussendurchmesser aufweist;

Fig. 40 -

einen Längsschnitt einer alternativen Ausführungsvariante eines erfindungsgemässen luftdicht verschlossenen Behälters in der Form einer Spritze, welche nadelseitig mit einer Glasfolie verschlossen ist; und

Fig. 41 -

einen Längsschnitt einer alternativen Ausführungsvariante eines erfindungsgemässen luftdicht verschlossenen Behälters in der Form einer Spritze, welche nadelseitig mit einer Glaswand verschlossen ist.

In the following, the inventive method for carrying out a chemical reaction and the inventive set of substances containing containers will be described in detail with reference to some embodiments. Show it:

Fig. 1 -

a longitudinal section of an embodiment of an inventive airtight container containing a pre-dosed amount of a substance;

Fig. 2 -

a longitudinal section of the container of Figure 1, before it has been filled with the substance and sealed airtight.

Fig. 3 -

a longitudinal section of the container of Figure 2, after the substance has been filled.

Fig. 4 -

a sectional view of an apparatus for carrying out a chemical reaction by means of inventive container, which are destroyed by a rotating magnetic stirrer;

Fig. 5 -

a perspective view of the apparatus of Fig. 4;

Fig. 6 -

a sectional view of an alternative apparatus for carrying out a chemical reaction by means of inventive container, which are destroyed by a rotating magnetic stirrer;

Fig. 7 -

a sectional view of another alternative apparatus for performing a chemical reaction by means of inventive container, which are destroyed by a needle;

Fig. 8 -

a longitudinal section of an embodiment of a container according to the invention, from which a container wall part has been pierced with a needle, which is currently supplying a solvent;

Fig. 9 -

a longitudinal section of the container and the needle of Figure 8, wherein the needle has absorbed the solvent with the substance dissolved therein.

Fig. 10 -

a longitudinal section of the container and the needle of Figure 8, wherein the needle has pierced the puncture site opposite container wall part and releases the solution with the substance.

Fig. 11 -

a longitudinal section of the container and the needle of Fig. 8, wherein, as an alternative to the dargestellen in Fig. 10 variant, the needle has been pulled out of the container and releases the solution with the substance next to it;

Fig. 12 -

a longitudinal section of the container and the needle of Fig. 8, wherein, as an alternative to the dargestellen in Figs. 9-11 variants, the needle without prior absorption of the solvent with the dissolved substance that the injection site opposite Pierced container wall part;

Fig. 13 -

a longitudinal section of the container and the needle of Figure 12 after pulling out the needle from the container.

Fig. 14 -

a longitudinal section of an alternative embodiment of an inventive airtight container containing a pre-dosed amount of a substance;

Fig. 15.1

to 15.4 - the production of container blanks for containers according to Fig. 14 in various process steps;

Fig. 16 -

a perspective view of a part of a hand-held or robotic apparatus, which are sealed with a pre-dosed amount of substance filled containers airtight;

Fig. 17 -

a perspective view of a part of an alternative or manually guided by a robot apparatus, which is sealed with a pre-dosed amount of a substance filled containers under an inert atmosphere airtight;

Fig. 18 -

a perspective view of an embodiment of an inventive set of 8 substances containing containers, which are mounted in a frame;

Fig. 19 -

a perspective view of an alternative embodiment of an inventive set of 96 substance-containing containers which are held in a rack;

Fig. 20 -

a perspective view of an alternative embodiment of an inventive airtight container in the form of a cuboid;

Fig. 21 -

a sectional view of an alternative embodiment of an inventive airtight container in the form of a ball;

Fig. 22 -

a longitudinal section of an alternative embodiment of an inventive airtight container in the form of a cylinder, which has a predetermined breaking point in the middle;

Fig. 23 -

a longitudinal section of an alternative embodiment of an inventive airtight container in the form of a cylinder, which is provided on the outside with a bar code;

Fig. 24 -

a longitudinal section of an alternative embodiment of an inventive airtight container in the form of a cylinder, which is provided on the outside with a chemical formula;

Fig. 25 -

a longitudinal section of an alternative embodiment of an inventive airtight container in the form of a cylinder, which is glued together in the middle;

Fig. 26 -

a longitudinal section of an alternative embodiment of an inventive airtight sealed container having two predetermined breaking points;

Fig. 27 -

a perspective view of 96 container blanks, which are held in a rack and each filled with a pre-dosed amount of a substance and are covered with a thin glass plate;

Fig. 28 -

the welding of the thin glass plate to the 96 container blanks according to FIG. 27 with the aid of a fire-resistant plate;

Fig. 28.1 -

an enlarged detail of Figure 28, showing an annular hole in the fire-resistant plate.

Fig. 29 -

a perspective view of the obtained according to Figures 27, 28 and 28.1 sets or kits of 96 substances containing containers;

Fig. 30 -

a perspective view of an alternative embodiment of an inventive set or kit of 96 substances containing containers with an upper and a lower thin glass plate;

Fig. 31 -

a perspective view of an alternative embodiment of a container according to the invention, which is to be closed by welding a thin lid;

Fig. 32 -

a longitudinal section of the container of Figure 31 in the closed state.

Fig. 33 -

a longitudinal section of the sealed container of Figure 32, which has been pierced with a needle which solvent for dissolving the substance admits.

Fig. 34 -

a perspective view of an apparatus according to Fig. 4, wherein here in the reaction solution, a not yet destroyed container containing a pre-dosed amount of a substance can be seen.

Fig. 35 -

a schematic perspective view of an apparatus of parallel reactors, which is added to a set of containers with predosed substances in parallel;

Fig. 36 -

a hollow glass rod which is used to make a blank;

Fig. 37 -

a hollow blank for producing a container with a very thin wall;

Fig. 38 -

a hollow glass rod, which is pulled out at a position on a length of about 15 cm to a very thin glass rod;

Fig. 39 -

the hollow glass rod of Figure 38, in which the part is cut out, which has a thin wall and a desired outer diameter;

Fig. 40 -

a longitudinal section of an alternative embodiment of an inventive airtight container in the form of a syringe, which is closed on the needle side with a glass sheet; and

Fig. 41 -

a longitudinal section of an alternative embodiment of an inventive airtight container in the form of a syringe, which is closed on the needle side with a glass wall.

FIG. 1

It comprises a cylindrical hollow body 3, which is hermetically sealed at the bottom by a spherical bottom 4 and at the top by a partially spherical lid 5 provided with a melting tip. The cylindrical hollow body 3 has everywhere the same diameter except for the bottom and top portions.

The wall thickness b _{1 of} the cylindrical hollow body 3 is in particular relative to the outer diameter d ₁ , which is for example 4 mm, small, for example, 0.03 mm. This can be achieved on the one hand, that the internal volume of given external masses is as large as possible, and on the other hand, if glass is used as the exclusive container material, the container 1 is already broken under the action of relatively low external forces and the pre-dosed substance 4 is released. Nevertheless, the container is still transportable. The cavity 6 is usually filled with air under normal pressure, with delicate substances 2 or generally advantageously with nitrogen, more preferably with argon.

A small outer diameter d ₁ is desirable so that the container 1 can be introduced through a small addition point as possible into a reaction vessel, in which often very special conditions must prevail. So that enough substance can be filled in the container 1, this is tube-shaped, for example, with a length of 50 mm, formed.

For the further description the following definition applies. Are reference numerals in a figure for the purpose of graphic clarity, but in the directly associated description text is not explained, reference is made to their mention in previous figure descriptions.

FIG. 2

The not yet filled with a pre-dosed amount of a substance 2 and not hermetically sealed container is also referred to as a blank 1 '. It consists of a cylindrical hollow body 3 ', which is hermetically sealed at the lower end by the bottom part 4. In the illustrated embodiment, the entire test tube-shaped blank 1 'is made of a single material. The material used is, for example, metal, in particular stainless steel, Hastelloy ^™ or a titanium alloy, plastic, in particular PTFE, another polyfluorinated plastic, polypropylene, polyethylene, natural stone, in particular granite or gneiss, ceramic, in particular Al ₂ O ₃ or MACOR ^™ , or a glass, in particular borosilicate glass 3.3. Glass is particularly advantageous because it is chemically inert to many chemicals and reaction mixtures used in chemical research and development, and after filling the pre-dosed amount of a substance 2, especially in very thin-walled blanks 1 ', relatively locally, in the opening area 8 at can not be melted down to high temperatures, since the locally applied heat for melting the glass, not least thanks to the reasonably acceptable thermal insulation of glass, in a tolerable for most chemical compounds mass is transferred to the pre-metered amount of substance 2 filled before melting ,

The filling of the substance 2 in the blank 1 'can be done for example with a commercially available dosing.

FIG. 3

The blank 1 "which has not yet been hermetically sealed and filled with the predosed amount of the substance 2 is airtightly sealed in the opening region 8. On the one hand, when the blanks 1 'are filled, an exactly (in mmol) predosed amount of a substance is introduced and, on the other hand, the blanks 1 'For the widest possible range of on the one hand different substances 2 and on the other hand different amounts to be used, normally creates a cavity 6 ", since the substance 2 is not after eg Volume, but according to the number of mmol predosed. Since many substances are air sensitive, i. sensitive to oxygen and / or water, it is often necessary to fill the cavity 6 "prior to melting with a chemically inert gas as possible, either nitrogen or argon is usually used for this, but other gases or gas mixtures are also present. For safety and unitary reasons, this process can also be generalized without analyzing the specific negative potentials mentioned for each substance 2. The filling of the cavity 6 "with a gas can be achieved in various ways. Before melting, e.g. argon is placed in the blank 1 "by means of a needle, which is placed at the upper end of a tube. Since argon is heavier than air and strikes at the bottom, this is particularly simple in the case of this gas the entire apparatus is placed in a space filled with an inert gas, with which the cavity 6 "under certain known conditions automatically filled with the inert gas.

FIG. 4

A classical apparatus 11 for carrying out chemical reactions comprises an attached reflux condenser 12 with a Rückflusskühlerkühlflüssigkeitsraum 26 and a Rückflusskühlerinnenraum 27, an oil bath 13 with Ölbadbehältern 14, a magnetic stirrer 15 shown only schematically, a magnetic stirrer (often called by chemists magnetic stirrer fish) 16 (here a two-step cylinder with a magnetic core, which with a layer of PTFE is coated). A container 1 is located shortly before being added to the apparatus for conducting a chemical reaction. From an already introduced and broken container, the shards 18 are shown.

The addition of the container 1 via a reaction vessel opening 19, which is open at the moment, but can be closed, for example, by a non-illustrated plug with a NS 14.5 cut. The container 1 is added through the not occupied by the reflux condenser 12 opening of the two-necked flask. The reflux condenser is likewise connected to the reaction vessel 21 via a standard NS 14.5 cut. At the upper end of the Rückfrlusskühlers another standard grinding NS 14.5 22 can be seen, which leads to an olive 23, which is provided with a hose 24. It is therefore advantageous to have a slight overpressure of argon, since then it is ensured that even with a short opening of the reaction vessel 21 at the reaction vessel opening 19 by removing a plug not shown inert conditions are present.

As described, a container 1 has already been added to the reaction vessel 21 which has already been destroyed by the magnetic stirrer 16 and the corresponding substance 2 has already been substantially completely released. The substance 2 is dissolved in the reaction mixture and can no longer be seen by eye.

Alternatively, the container 2 could also be added through the opening on the standard ground 22, wherein the Disadvantage has that then no argon counterflow would be on the apparatus 11.

The long relative to the outer diameter d ₁ shape of the cylindrical container 1 in this embodiment makes it possible to achieve a relatively large internal volume 10, without losing the advantage that the a pre-dosed amount of a substance 2 containing airtight container 1 after airtight closure by a relatively small opening 19 on the reaction vessel 21 can be supplied to this. This is often necessary because the container 1 containing a pre-dosed amount of a substance 2 must often be added during the reaction to the reaction mixture 17 and the outside of the interior of the reaction apparatus 11 should as far as possible be avoided. To achieve an absolutely inert atmosphere, the interior space 25 of the reaction apparatus 11, which contains gases or gas mixtures, is often filled, for example, with a chemically inert gas such as N ₂ or argon. This means that the larger the opening 19 of the reaction vessel 21, the greater the risk that the atmosphere in the reaction vessel 21 is adversely affected by the opening of the reaction vessel 21 necessary for feeding the vessel 1 through the atmosphere in the environment of the reaction vessel 21 becomes.

In WO 98/57738 reaction apparatuses are described, which allow in a simple way that the containers 1, e.g. can be added fully automatically under very precise conditions through relatively small openings.

FIG. 5

In the reaction mixture 217, a not yet destroyed, still hermetically sealed container 1, which contains a pre-dosed amount of a substance 2, can be seen. This Container can now be destroyed by switching on the schematically illustrated magnetic stirrer 15 with a specific frequency relatively targeted to a desired time. In this case, the exact nature of the container 1, ie, for example, its thickness, its material or its construction in addition to the frequency plays a crucial role. The container 1 may be such that it is destroyed or opened at the slightest movement or only after application of a large force.

The remainder of the apparatus 11 is the same as in FIG. 4, except that the coolant connection hoses 24 (see FIG. 4) and the argon connection (see FIGS. 23 and 24 in FIG. 4) are not shown for the sake of clarity.

FIG. 6

The illustrated alternative apparatus 111 comprises a reflux condenser 112 mounted on a reaction vessel 21 with a reflux condenser cooling space 126 and a reflux condenser interior 127, an oil bath 13 with an oil bath container 14, a shaking device 28 shown only schematically, airtightly closed just before being added to the reaction vessel 21 Container 101 with a pre-dosed substance 102 for carrying out a chemical reaction, a reaction suspension 117 and remnants 118 (indicated by a plurality of fragments) of a broken container 101. A first pre-dosed quantity of the substance 102 has already been released from the first container 101. A reaction vessel opening 19 is open at the moment, but can be closed by a non-illustrated plug with a standard cut NS 14.5. The reflux condenser 112 is connected to the reaction vessel 21 via a standard NS 14.5 cut 120. At the upper end of the reflux condenser another standard cut NS 14.5 122 can be seen, which allows an argon line (see Fig. 4, reference numerals 23 and 24) can be connected. The container 101 is thrown in this Ausführungsbeipiel without argon overpressure in the open reaction vessel 21.

As described, a container 101 has already been added to the reaction vessel 21, which has already been destroyed by shaking with the shaker 28, depending on the container stability, and has already substantially completely released the substance 102. Another container 101 is added under an argon countercurrent. The container 101 is destroyed in this embodiment so that it usually moves uncontrollably in the reaction solution, while once or more times the vessel wall 29 of the reaction vessel 21 is touched and thereby smashed. Since in this embodiment, the container 101 is made of relatively thin glass, this is done relatively easily and depending on the Schüttelfrequenz with very high reliability. The glass shards are simply left in the reaction solution, which in this case, however, at most negligibly affects the reaction in most cases. In addition, the broken glass are removed at the desired time. However, the most convenient, simplest and safest method is to leave the container remains 118 in the reaction suspension 117 until their work-up is carried out, where as a rule for other reasons either way must also be filtered. In a fully automatic apparatus, as described in WO 98/57738, even the filtration can take place at virtually any desired time.

In the reaction vessel 21 of the apparatus 111 may also be a generally filled under normal pressure container 101, for example, about normal pressure as described above introduced. If then on the reaction vessel 21, an overpressure is applied, the container shatters at a certain overpressure by itself.

FIG. 7

The apparatus 111 'largely corresponds to the apparatus 111 described in Fig. 6, with the exception that the Rückflusskühleranschlussschläuche 24 are not shown for clarity. In addition, no shaking device 28 is present, no second container is added and there are no remnants of a broken container. For this purpose, a container 201 is present, which is being pierced by a needle 30 controlled manually or by a robot, whereby the substance 302 has not yet been released, but the airtightness of the container 201 is just canceled. The container 201 has the shape of a relatively flat, for production technical reasons at the edges and ends slightly rounded cuboid. This form is preferred for the variant shown in this figure for releasing the substance 302 from the container 201, since the needle 30 can hit the container 201 better. But there are various other variants of containers conceivable, especially when using special needles, which have a larger outer diameter c and instead of a needle tip 32 has a flat lower end.

FIG. 8

The illustrated inventive container 301 comprises a cylindrical container wall 203 with wall thickness b ₂ , for example 0.03 mm, a spherical bottom part 204 and a spherical cover part 205. In the container 301 a predosed amount of a substance 402 is arranged, above which a cavity 206 is located. By the insertion of a hand-held or by a sampler or robot out Needle 130 through a container wall portion 34, which in this case is a part of the lid portion 205, in the container 301, this has just been irreversibly opened. The needle 130 is supplying a solvent 35 in which the substance 402 is dissolved.

Not shown is the bracket, which is necessary so that the container can be safely and cleanly pierced. This holder is for example integrated in a manual tool or in a robot, eg on the floor of the robot, usually a rack for holding the containers, in particular in the cases in which the sequence procedure described in FIGS. 9 and 11 is used come. It is thus also stated that FIGS. 8, 9 and 11 represent a sequence of working sequences, while FIGS. 8, 12 and 13 or 8, 9 and 10 each represent an alternative operating sequence with which a substance in dissolved form, instead of as in the preceding figures in pure form, for example, can be added in a reaction vessel. The not shown support of the container 301 at the end 8, 12 and 13 is preferably integrated at the bottom of the robot in a rack for holding the container as in the sequence 8, 9 and 11 and that at the end 8, 9 and 10 is preferably directly in Gripper integrated (in the chamber in which the container is received). Also conceivable for the last sequence is a holder directly above an opening or a potential opening of the reaction vessel or such in the reaction apparatus itself, in particular when absolutely reliable conditions are required during the addition of the dissolved substance. Particularly in the case of the drainage variant according to FIGS. 8, 9 and 10, the unillustrated gripper or the needle 130 with the container 301 can carry out the entire process within the apparatus, again in particular when absolutely controllable conditions are required.

In the following, starting from the situation according to FIG. 8 in connection with FIGS. 9-13, the various process variants will be described, wherein the processes themselves are no longer completely described.

FIG. 9

The solvent 35 has already dissolved the substance 402 and the needle 130 has completely absorbed the resulting solution 33. The term "solution" as used herein also includes suspensions, emulsions, a mixture of a liquid and solid particles which are e.g. by means of prior shaking in suspension, ie an imbalance condition, etc. For safer and better solution preparation, the solution 33 or a part thereof can be drained off again and sucked up again, possibly even several times. Thus now various options are open.

FIG. 10

The needle 130 has pierced the puncture hole 38 opposite bottom portion 204 and now gives the sucked solution 33 again, for example, in a reaction apparatus, a reaction vessel or an intermediate container.

FIG. 11

As an alternative to the method step shown in FIG. 10, the needle 130 with the sucked-up solution 33 has been pulled out of the container 301 here and now releases the solution 33 at a different location substantially completely or aliquoted at several other locations. The container can be held eg in a robot arm and then ejected or simply be held in a rack. The substantially completely empty container is then usually thrown away.

FIG . 12 .

The e.g. by a robot guided needle 130 has in this variant after forming the solution 33 by dissolving the substance 402, the piercing site opposite bottom portion 204 pierced by a simple downward movement.

FIG. 13

Starting from the situation illustrated in FIG. 12, the needle 130 is pulled out of the container 301 by hand or controlled by a robot. This leaves not only a Ausstichloch 37 in the bottom part 204 but also a puncture hole 38 in the cover part 204, which automatically ensures a pressure equalization in the container at the outlet of the solution 33.

FIG. 14

In this embodiment, the airtight container 401 according to the invention comprises a pre-metered quantity of a substance 302. It comprises a cylindrical hollow body 303 at the bottom through a partially spherical, enamel-topped bottom 304 and at the top through a partially spherical, enamel-topped lid 305 is hermetically sealed. The cylindrical hollow body 303 has the same diameter throughout except for the bottom and top portions. The wall thickness b _{3 of} the cylindrical hollow body 303 is in particular relative to the outer diameter, which is for example 4 mm, small, for example, 0.04 mm. The cavity 306 is typically filled with air under normal pressure, with delicate substances 302 or, more generally, advantageously with nitrogen, more preferably with argon.

Otherwise, what has been said in connection with FIG. 1 essentially applies.

FIGS. 15.1 to 15.4

FIGS. 15.1 to 15.4 show the production of container blanks for containers according to FIG. 14 in various method steps. It is, as shown in Fig. 15.1, assumed by a top and bottom open, relatively thin-walled glass cylinder 40 with wall thickness b ₄ , for example, 0.05 mm.

According to FIG. 15.2, the glass cylinder 40 is melted at a certain point with a highly focused, fine-jet flame 44 which is emitted by a flame detector 45 and guided and controlled by hand or by a robot (not shown). The flame 44 is generated by burning off a common gas which is supplied via lines 47, 48. Thus, on the one hand, an open container blank 301 'with the bottom part 304 according to FIG. 15.3 and, on the other hand, a downwardly closed, about the length of the blank 301' shorter, hollow glass cylinder 40 'is formed.

In the next step, as shown in Figure 15.3, from the glass cylinder 40 'with a flame 44', which is discharged from a flame detector 45 ', a lower part 42, which has about twice the container length, separated. The flame detector 45 'may be the same as the flame detector 45. From the remaining glass cylinder part further lower parts 42 can be separated.

Thereafter, the lower part 42, as shown in Fig. 15.4, halved with a diamond blade 46, whereby two unilaterally open container blanks 41 corresponding to the container blank 301 'arise.

FIG. 16

For filling and closing of container blanks according to FIG. 2, the blanks 1 ', 1 ", 1"', etc. are supported in the illustrated embodiment in holes 63 of a frame 61. In the blanks 1 ', 1 ", 1' '', etc., a precisely pre-metered amount of a substance 402 ', 402", etc. is filled in each case. Subsequently, the filled blanks 1 ', 1 ", 1"', etc. by means of a hand or by a robot 62, which is schematically represented by the spatial axes, guided melting apparatus 60 per ever sealed to an airtight container 1 according to FIG ,

FIG. 17

For filling and closing container blanks according to FIG. 2, the blanks 1 ', 1 ", 1"', etc. are supported in holes 67 of a frame 65 in this alternative embodiment. A precisely predosed amount of a substance 502 ', 502 ", etc. is introduced into each of the blanks 1', 1", 1 "', etc. Subsequently, the filled blanks 1', 1", 1 "', etc. are filled. by means of a hand-held or by a robot 66, which is shown schematically by the spatial axes, guided melting apparatus 64 each melted to a substance 502 filled airtight container 1 according to FIG. 1.

In contrast to the exemplary embodiment illustrated in FIG. 16, the closure of the container blanks takes place here under a transparent cube 68, for example made of Plexiglas or polycarbonate. In this case, the free space in the cube 68 is completely filled with a chemically relatively inert gas, for example nitrogen, more advantageously a noble gas, for example argon, whereby it results that the space not occupied by the predosed substance 502 is airtight Finally closed container 1 is also filled with this chemically relatively inert gas.

In addition, there are other variants, not shown, to achieve that the container 1 are finally filled next to the desired substance with the chemically relatively inert gas. For example, just before melting and possibly also during melting argon, which is heavier than air and consequently accumulates on the substance, e.g. via a mounted on the melting apparatus 60 or 64 needle, which is attached to a gas line, in the blanks 1 ', 1 ", 1"', etc. are blown.

Although the variant shown in Figure 17 with a chemically relatively inert gas under a cube 68 has the disadvantage that usually more gas is needed, but the often decisive advantage that e.g. with air or the oxygen contained therein self-igniting substances 502 ', 502 ", etc. or hydrolysis-sensitive substances 502', 502", etc., can be filled safely and while maintaining the quality of the substances.

FIG. 18

Containers Eight substances 602, 702, etc. are supported here in holes 71 in a frame 70. In the filling of the blanks 1 ', 1 ", 1''', etc., as shown in FIGS. 16 and 17 is advantageously but not necessarily per frame or group of frames always the same substance, but advantageously not necessarily in the always same pre-dosed quantity, since this simplifies and speeds up the filling procedure, especially if it is fully automated, these racks are then stored and, if required, eg from a commercially available storage robot to a set 69 of containers 1 with different Substances 602, 702, etc. assorted. For certain applications, it is advantageous to use racks of the same substances but not necessarily in the same predosed amount. In this case, only different racks form a set of containers with different substances.

FIG. 19

The alternative set 72 illustrated here comprises containers 1 containing 96 substances 802, 802 ', etc., which are held in holes 74 in a rack 73. In the following applies to Fig. 18 said.

FIG. 20

An alternative embodiment of an inventive hermetically sealed container 501, which contains a pre-dosed amount of a substance 902, has the shape of a cuboid 403 with a relatively thin wall thickness b ₅ , eg 0.02 mm, an inner volume 406, which is not taken up by the substance 402 is, a cover part 405 and a bottom part 404th

FIG. 21

In this alternative embodiment variant, the airtight container 601 according to the invention, which contains a predosed amount of a substance 1002, has the form of a sphere 503 with a relatively small wall thickness b ₆ , eg 0.03 mm. Also, this application example is comparable in terms of ease of use with the container 1 described in Fig. 1, although the volume compared to the smallest cross-section is significantly smaller than the cylindrical container 1 of Fig. 1 and thus the maximum predosettable substance amount 1002 is smaller ,

However, for certain applications, especially in the nanomolar range, this container 601 has decisive advantages. For example, it may also be "pseudorandom", e.g. are dosed directly into a reaction vessel by means of lines having a diameter which corresponds for example to four times the ball diameter, in particular if a multiplicity of identical containers 601 are used per reaction and the total amount of substance is measured "quasivolumetrically". Although the accuracy suffers, but this does not necessarily have to be relevant for a large number of balls, the speed is considerably increased. In addition, the accuracy can be made by marketable optical detection and counting systems again to a high degree.

FIG. 22

In this alternative embodiment, the airtight container 701 according to the invention, which contains a predosed amount of a substance 1102, comprises a cylindrical hollow body 603 with a wall thickness b ₇ , eg 0.5 mm, which is defined below by a spherical bottom 504 and at the top by a partially spherical, provided with a melting tip cover 505 is hermetically sealed. The cavity above the substance 1102 is designated 506. In the middle of the container 701, the cylindrical hollow body 603 has a constriction 76 and a slightly smaller container wall thickness and thus a predetermined breaking point 75.

FIG. 23

In this alternative embodiment variant, the airtight container 801 according to the invention, which contains a predosed amount of a substance 1202, comprises a cylindrical hollow body 703 with a small wall thickness b ₈ , for example, 0.04 mm, which is hermetically sealed at the bottom by a spherical bottom 604 and above by a partially spherical, provided with a melting tip cover 605. The cavity above the substance 1202 is designated 606. The cylindrical hollow body 703 is provided on the outside with a bar code 77 for identifying the substance 1202 contained in the container, its quantity, its quality, etc. The bar code 77 is here incised in the container wall of glass, which has the advantage that no additional material must be used, which would also be chemically inert again depending on the application.

FIG. 24

In this alternative embodiment, the airtight container 901 according to the invention, which contains a predosed amount of a substance 1302, comprises a cylindrical hollow body 803 with a small wall thickness b ₉ , eg 0.02 mm, which is defined below by a spherical bottom 704 and at the top by a partially spherical, provided with a melting tip cover 705 is hermetically sealed. The cylindrical hollow body 803 is provided on the outside with a chemical formula 78 for identifying the substance 1302 located in the container. The chemical formula 78 is here incised in the container wall of glass, which has the advantage that no additional material must be used, which would also be chemically inert again depending on the application.

It is particularly advantageous to provide a container both with the bar code 77 shown in FIG. 23 and with the chemical formula 78, since for the user on the one hand a name with a known meaning and on the other hand a barcode loadable with much more information Available, but which in contrast to the chemical formula by the user is usually not readable without auxiliary means.

FIG. 25

In this embodiment variant, the airtight container 1001 according to the invention contains a predosed amount of a substance 1302 and above it a cavity 806. It comprises a cylindrical hollow body 903 with a wall thickness b ₁₀ , eg 0.5 mm, which is provided below by a partially spherical, with a melting tip Bottom 804 and above by a partially spherical, provided with a melting tip cover 805 is hermetically sealed. At a predetermined separation point 175 approximately in the middle of the container 1001, this has an adhesive point 79 between two container parts, which can be dissolved, for example, by a solvent or a reaction mixture, so that the container is opened.

FIG. 26

In this embodiment, the inventive airtight container 1101 contains a pre-dosed amount of a substance 1402 and about a cavity 906. It comprises a cylindrical hollow body 1003 with a diameter d ₁₁ , for example 4 mm, and a wall thickness b ₁₁ , for example, 0.5 mm, the bottom is closed by a partially spherical, provided with a melting tip bottom 904 and above by a partially spherical, provided with a melting tip lid 905 airtight. In the vicinity of the lid 905 and the bottom 904, the cylindrical hollow body 1003 each has a constriction 82 and a slightly smaller container wall thickness and thus in each case a predetermined breaking point 275.

This embodiment has the advantage over the one shown in Fig. 22 that the substance 1402 can be released faster from the container. In particular, when the substance is dissolved out with the aid of a solvent, problems may arise in the container 701 of FIG. 22 in that capillary effects may occur, especially with small internal cylinder diameters, and a local underpressure delays or even prevents further leakage of liquid or dissolved substances. This disadvantage is greatly reduced with the container 1101, since it is opened at two predetermined breaking points 275.

There were also produced containers with even more predetermined breaking points. In the case of glass, the easiest way to make these is to scrape the desired spot (over a certain angle or all around) with a diamond cutter.

FIGS. 27 to 29

FIGS. 27, 28 and 28.1 show the production of a set 95 or kit according to the invention of containers 1501 containing 96 substances according to FIG. 29.

According to FIG. 27, 96 blanks 1 'having a cylindrical hollow body 3 are initially arranged by means of springs 1500 in holes 86 of a rack 83 and each filled with a predosed amount of a substance 1502. Thereafter, all blanks 1 'covering, relatively thin glass plate 87 according to arrow 84 on the open side of the blanks 1' placed. The springs 1500 ensure that all the blanks 1 'rest against the glass plate 87.

A thicker, heat-insulating and fire-resistant plate 88 is then placed on the glass plate 87 as shown in FIGS. 28 and 28.1, which has annular holes 89 exactly at the locations below which the edges of the blanks 1 'are filled with the predosed substances 1502 lie. The annular holes 89 have the same outer diameter e ₁ and the same inner diameter e ₂ as the blanks 1 'of the container 1501. The heat-insulating and fire-resistant cores in the holes 89 are held by wire-like connections 90. Heat is then generated by means of an apparatus 2000 which produces 96 flames 2001 and fed through the annular holes 89 to the glass plate 87, whereby the blanks 1 'of the containers 1501 are melted with their upper edge against the glass plate 87.

The described procedure results in the inventive set of 96 containers containing pre-dosed substances shown in FIG. 29 or a corresponding kit with 96 containers containing the same substance which together with at least one other container with another substance contains a set of substances according to the invention Forms containers. Individual containers 1501 can be easily broken off this set 95. Depending on the thickness f _{1 of} the glass plate 87, the cover 1005 of a single container 1501 thus formed forms a predetermined breaking point or zone, in particular if the wall thickness g of the cylindrical part 3 of the container 1501 is significantly greater.

As an alternative to the melting of the glass plate 87 to the blanks 1 'of the container 1501 and a sticking is conceivable.

FIG. 30

In this alternative embodiment of a kit 195 according to the invention or a kit, the 96 hermetically sealed containers 1601 each comprise a predosed amount of a substance 1602, a cylindrical hollow body 1603, a lid 1605 and a bottom 1604 Cavity over substance 1602 is labeled 1606. Lids 1605 and bottoms 1604 are formed by fusing or adhering each of a thin glass plate 287 to the bottom and top of the container blanks. In this set 195, the hermetically sealed containers 1601 each having a pre-dosed substance 1602 are held together by the two plates 287 and can be easily broken. Depending on the thickness f _{2 of} the glass plates 287, the cover 1605 and the bottom 1604 of a single container 1601 form a predetermined breaking point or zone.

FIGS. 31 and 32

An alternative embodiment of a container 1201 according to the invention comprises a cylindrical hollow body 1203 with wall thickness b ₁₂ , for example 0.7 mm, a spherical bottom 1204 and a threaded part 1207 adjoining the latter on the latter. The container 1201 contains a predosed amount of a substance 1202 and above it a cavity 1206. He is by welding or gluing a relatively thin lid 1205, preferably made of the same material, closable. The threaded portion 1207 allows, if desired, the Autschrauben a removable safety cap. This can be provided with a septum and already screwed on before the first piercing.

Alternatively, the lid of the container can be attached via a well-defined negative pressure in the container itself to this. Once the container is placed in the reaction vessel and this is placed under a negative pressure which is comparable to that of the interior of the container, the lid dissolves by itself or at the latest while shaking or stirring the reaction vessel.

In another embodiment, the containers 1201 are made of a metal, e.g. Stainless steel, manufactured and pressure sealed in the opening area with a commercially available rupture disc. The rupture disk may be closed by means of a cap, e.g. also made of stainless steel, can be screwed onto the container 1201.

FIG. 33

The container 1201 according to FIG. 32 has here been pierced with a needle 798 in the region of the lid 1205, which forms a predetermined breaking zone. The needle 798 now releases solvent 1208 to dissolve the predosed substance 1202. The continuation possibilities arise correspondingly from FIGS. 9 to 13.

FIG. 34

The illustrated apparatus 11 corresponds to that shown in FIG. 5, but a container 1301 containing a pre-dosed quantity of a substance 1302 has been introduced into the reaction vessel and corresponds to the container 1201 according to FIG. 32. By switching on the magnetic stirring motor 15 shown schematically, the container 1301 has been irreversibly opened by the magnetic stirring bar 16 in the region of the cover designed as a predetermined breaking zone 1305, namely at a desired time. In this case, the exact nature of the container 1301 or the predetermined breaking zone 1305, ie the thickness and the material or the construction of the predetermined breaking zone 1305, in addition to the frequency with which the magnetic stirring bar 16 rotates, plays a decisive role. Thus, containers 1301 or predetermined breaking zones 1305 may be designed so that they are opened at the slightest movement or only after application of a relatively large force. Depending on the design is also a continuous or even chamberwise opening conceivable. In addition, the bottom may be formed as a predetermined breaking zone.

FIG. 35

Sixteen reaction vessels 121 are supported here in a frame 140. Sixteen hermetically sealed containers 297 with pre-metered quantities of substances placed in a plate 290 or in a plate with through-holes, e.g. with a film, in particular aluminum foil, subjected and possibly also coated, can be pressed simultaneously by means of a plate 211 in the reaction vessels 121 (manually or with a robot). It is also possible for the containers 297 to be individually, jointly or group-controlled by means of unillustrated punches (which are necessary in a foil-coated and coated plate) which may be attached to a plate or may be controlled by hand or by a robot. individually, collectively or in groups in the reaction vessels 121 to press. The containers 297 can be opened simultaneously.

FIGS. 36 to 39

FIGS. 36 to 39 show the production of a very thin glass rod 2004, which can then be used, for example as described in connection with FIGS. 15.1 to 15.4, for producing blanks for containers of very small wall thickness according to the invention.

A hollow glass rod 99 with a relatively large wall thickness b ₁₃ of, for example, 2 mm, as shown in FIG. 36, is heated at a location 2003 according to FIG. 37 and blown out to the blank 99 'by hand or by machine. This is then shown in FIG. 38 at the point 2003 on a length of about 15 cm to a very thin, for example, 0.04 mm thin glass rod with outer diameter d ₁₃ , the part of the blank 99 ", the thin glass rod 2004 is then cut out as shown in FIG.

FIG. 40

In this alternative embodiment, the airtight container 1701 according to the invention, which contains a predosed amount of a substance 1702, is designed in the form of a syringe and comprises a substantially cylindrical hollow body 1703 with a rounded bottom 1704. The bottom 1704 has a through opening 1705, into which a hollow needle 1706 is welded. The opening of the hollow needle 1706 is hermetically sealed by a glued or welded thin glass foil 1707. Over the substance 1702, the cylindrical hollow body 1703 is hermetically sealed by a glued or welded thin glass film 1708. The cylindrical hollow body 1703 and the bottom 1704 are preferably made of glass, while the hollow needle 1706 is preferably made of metal.

By displacing a syringe plunger 1709 in the direction of the arrow, the glass foil 1708 is destroyed, the substance 1702 is pressed downwards and thereby likewise the glass foil 1707 is destroyed, so that the substance 1702 can be released through the hollow needle 1706.

Alternatively, instead of the thin glass sheet 1708, a thin glass wall may be provided as part of the container wall, in which case the container 1701 is filled either through the through opening 1705 or before its walls are completed.

FIG. 41

In this alternative embodiment variant, the airtight container 1801 according to the invention, which contains a predosed amount of a substance 1802, is in turn formed in the form of a syringe and comprises a substantially cylindrical hollow body 1803 with a rounded bottom 1804 and a flange 1807 at its upper end. The bottom 1804 has a blind hole 1805 into which a hollow needle 1806 is welded. The cylindrical hollow body 1803 is airtightly closed against the hollow needle 1806 through the thin remainder of the bottom wall 1804 and on the other hand over the substance 1802 by a thin glass foil 1808 glued or welded to the flange 1807. The cylindrical hollow body 1803 and the bottom 1804 are preferably made of glass, while the hollow needle 1806 is preferably made of metal.

By moving a syringe plunger 1809 in the direction of the arrow, the glass foil 1808 is destroyed, the substance 1802 is pressed down and thereby the thin remainder of the bottom wall 1804 over the hollow needle 1806 is destroyed, so that the substance 1802 can be released through the hollow needle 1806.

Alternatively, instead of the thin glass sheet 1808, a thin glass wall may be provided as part of the container wall, in which case the container 1801 is filled before completion of its walls.

Table 1 below lists a set of 50 substances which have been packaged airtight in 7 different mmol quantities in glass containers according to FIG. 1. The percentages in column 2 are purity data. The mmol amounts are adjusted for purity. Of each substance, at least 96 containers have been made in any amount. Various other embodiments of containers with substances in different amounts according to the claims were realized. No substance Amount of substance in a container with respect to mmol content 1 Cyclohexanol (C ₆ H ₁₂ O) 29100, 99%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 2 Sodium hydride (NaH) 71620, 55-65%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 3 Benzyl bromide (C ₇ H ₇ Br) 13250, 98%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 4 aq. HBr 48% (mmol amounts are given for HBr), 18710, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 5 N, N-dimethylformamide (C ₃ H ₇ NO) 40228, 99.5%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 6 Sodium borohydride (NaBH ₄ ) 71321, 96%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 7 Lithium aluminum hydride (LiAlH ₄ ) 62420, 97%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 8th Boron tribromide (BBr ₃ ) 15690, 99%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 9 Boron trifluoride ethyl etherate BF _3. Et ₂ O 15719, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 10 Butyllithium solution, (C ₄ H ₉ Li) 20161, ~ 10M (mmol amounts are given with respect to C ₄ H ₉ Li) in hexane, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 11 Tert-butyl-lithium solution (C ₄ H ₉ Li) 20190, ~ 1.5M (mmol amounts are given with respect to C ₄ H ₉ Li) in pentane, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 12 Tert-butylmagnesium chloride solution (C ₄ H ₉ MgCl) 20194, ~ 1.6M (mmol amounts are given in terms of C ₄ H ₉ MgCl) in tetrahydrofuran, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 13 Lithium borohydride, (LiBH ₄ ) 62725, 95%, Riedel de Häen 00:01 00:05 0.1 0.5 1.0 5.0 10.0 14 2-Diisopropylaminoethylamine (C ₈ H ₂₀ N ₂ ) 38320, 97%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 15 Lithium diisopropylamide (C ₆ H ₁₄ LiN) 62491, -2.2M (mmol amounts are given with respect to C ₆ H ₁₄ LiN) in THF / heptane / ethylbenzene, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 16 Aluminum chloride (AlCl ₃ ) 06220, 99%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 17 Methanesulfonyl chloride (CH ₃ SO ₂ Cl) 64260, 99%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 18 Acetyl chloride (CH ₃ COCl) 00990, 99%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 19 Acetic anhydride, (CH ₃ CO) ₂ O 45830, 99.5%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 20 Trifluoroacetic anhydride, (CF ₃ CO) ₂ O 91720, 98%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 21 Toluene-4-sulfonic acid monohydrate, (C ₇ H ₈ O ₃ SH ₂ O) 89760, 99%, Fluka 00:01 00:05 0.1 0.5 -.0 5.0 10.0 22 Toluene-4-sulfochloride (C ₇ H ₇ SO ₂ Cl) 89730, 99%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 23 Aluminum bromide (AlBr ₃ ) 06180, 98%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 24 Methyllithium solution, (CH ₃ Li) 67740, ~ 1.6M in diethyl ether, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 25 Methylmagnesium bromide solution, (CH ₃ MgBr) 67742, ~ 3M in diethyl ether, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 26 Ethylmagnesium bromide solution (CH ₃ CH ₂ M ₉ Br) 46103, ~ 3M in diethyl ether, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 27 Titanium (III) chloride (TiCl ₃ ) 89487, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 28 Diethylaluminum chloride, (CH ₃ CH ₂ ) ₂ AlCl 31724, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 29 Diethylaluminum hydride, (CH ₃ CH ₂ ) ₂ AlH 31728, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 30 Diethylamine (CH ₃ CH ₂ ) ₂ NH 31729, 99.7%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 31 Sodium, (Na) 71172, 98%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 32 Potassium, (K) 60030, 98%, Riedel de Häen 00:01 00:05 0.1 0.5 1.0 5.0 10.0 33 Lithium, (Li) 62361, 99%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 34 Bromine (Br ₂ ) 16040, 99.5%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 35 Imidazole (C ₃ H ₄ N ₂ ) 56750, 99.5%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 36 Iodine (I ₂ ) 57650, 99.8%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.-0 37 Sodium hydroxide (NaOH) 71691, 98%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 38 Thiophenol (C ₆ H ₅ SH) 89021, 98%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 39 Nitromethane (CH ₃ NO ₂ ) 73479, 97%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 40 Sodium iodide, (NaI) 71710, 99.5%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 41 Palladium (II) acetate (CH ₃ COO) ₂ Pd 76044, 47%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 42 Palladium chloride (PdCl ₂ ) 76050, 60%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 43 Palladium on charcoal, (Pd) 75990, 10% (mmol amounts are given in terms of Pd), Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 44 Tetrakis (triphenylphosphine) palladium (Pd [(C ₆ H ₅ ) ₃ P] ₄ 87645, 97%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 45 Triphenylphosphine (C ₆ H ₅ ) ₃ ^P 93090, 99%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 46 Samarium (II) iodide solution (SmI ₂ ) 84453, ~ 0.1M (mmol amounts are given as SmI ₂ ) in tetrahydrofuran, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 47 Triethylamine, (CH ₃ CH ₂ ) ₃ N 90340, 99.5%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 48 Methyl iodide (CH ₃ I) 67690, 99.5%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 49 Osmium tetroxide (OsO ₄ ) 75631, 99.9%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0 50 3-chloroperbenzoic acid (C ₇ H ₅ ClO ₃ ), 25800, 70%, Fluka 00:01 00:05 0.1 0.5 1.0 5.0 10.0

It basically does not matter if the system is up. for example, 2 x 10 ^-x 3 ^-x x 10, 3.01, 10 x or ^-x as described in Table 4, 1.1 x 10 ^-x mmol etc. or, for example a composition of containers with 1 x 10 ^-x, 2 x 10 ^{- x} and 5 x 10 ^-x etc. or as described in the above table, to 1 x 10 ^-x and 5 x 10 ^-x builds. In the examples given here, x is usefully an even number.

In the following, three examples of chemical reactions that have been carried out in a classical manner and according to the invention will be described.

Example 1 : Alkylation of an Alcoholate with an Alkyl Halide (Williamson Ether Synthesis)

The chemist has planned the following reaction, referred to as Williamson's ether synthesis by experts. The regulation described below corresponds to the classical execution of the reaction, ie the implementation without using containers according to the invention and without using the process according to the invention:

a) Strictly classical experiment

10 ml of solvent (dimethylformamide) were initially charged with a commercially available disposable syringe in the inertized reaction vessel. Thereafter, the alcohol 1 (0.1002 g, 0.106 ml, 1 mmol) was added to the reaction mixture. Subsequently, sodium hydride (0.044 g of a 60% dispersion in oil, 1.1 mmol, 1.1 eq.) Was added to the reaction mixture. The reaction mixture was heated to 40 ° C for 15 minutes and then benzyl bromide 2 (0.171 g, 0.109 mL, 1.0 mmol, 1.0 eq.) Was added at room temperature. The reaction mixture was stirred for 4 hours at room temperature. Subsequently, 10 M HBr _{aq was} added (0.2 ml, 2 mmol, 2 eq., With respect to HBr), the mixture was filtered and the filtrate was evaporated in vacuo.

b) New procedure with reagent containers mixed with classical proportions

This reaction was now carried out using the process according to the invention and a container according to the invention filled with benzylic bromide. The following describes the deviations from the classical method:

In this embodiment of the inventive method, 10 ml of solvent (dimethylformamide) were introduced with a commercially available disposable syringe in the inertized reaction vessel. Thereafter, the alcohol 1 (0.1002 g, 0.106 ml, 1 mmol) was added to the reaction mixture. Sodium hydride (0.044 g of a 60% dispersion in oil (1.1 mmol, 1.1 eq.) Was added to the reaction mixture, the reaction mixture was heated at 40 ° C. for 15 minutes and then a 1.0 mmol container filled with benzyl bromide (cf. 0.171 mg, 0.109 ml, 1.0 mmol, 1 eq.) Was added to the reactor at room temperature The moving magnetic stirrer automatically destroyed the container in this embodiment, releasing the benzyl bromide in the reaction mixture and allowing it to react with the already submitted reactants. The reaction mixture was stirred for 4 hours at room temperature, then 10 M HBr _{aq were} added (0.2 ml, 2 mmol, 2 eq., Relative to HBr) and the filtrate was evaporated in vacuo.

c) New procedure with reagent containers, but added solvent classic

This reaction was carried out using the method according to the invention and the container according to the invention according to Table 1. Only the solvent was added classically. The following describes the deviations from the classical method:

In this simple embodiment of the method, as described in independent claim 1, the solvent (dimethylformamide) was introduced with a commercially available disposable syringe in the inertized reaction vessel. Then, the alcohol 1 (0.1002 g, 0.106 ml, 1.0 mmol), filled in a 1.0 mmol container, by hand into the reaction vessel thrown (short manual Opening the reaction vessel during the addition). The moving magnetic stirrer automatically destroyed the container in this embodiment. The alcohol was subsequently released in the submitted dimethylformamide and dissolved. The experimenter then added a 1.0 mmol container of sodium hydride (0.024 g, 1.0 mmol, 1.0 eq). Since he had to use 1.1 equivalent as described above, another 0.1 mmol container of sodium hydride (0.0024 g, 0.1 mmol, 0.1 eq.) Was added These containers were also automatically destroyed and the sodium hydride was suspended in dimethylformamide The reaction mixture was heated at 40 ° C. for 15 minutes and then a further 1.0 mmol container of benzyl bromide (0.171 mg, 0.109 ml, 1.0 mmol, 1.0 eq The reaction mixture was stirred for 4 hours at room temperature, then two 1.0 mmol containers with 10 M HBr _aq (each 0. ml, 1.0 mmol., In terms of HBr) were added in succession to the solution, the filtrate was filtered off and the filtrate was filtered off evaporated.

d) New procedure with reagent and solvent containers

This reaction was carried out using the method according to the invention and the container according to the invention according to Table 1. The solvent, dimethylformamide (14.62 g, 10.2 ml, 0.2 mol), was filled in four 0.05 mol containers added. Subsequently, the alcohol 1 (0.1002 g, 0.106 ml, 1.0 mmol), filled into a 1.0 mmol container, was thrown by hand into the reaction vessel (short manual opening of the reaction vessel during the addition). The moving magnetic stirrer automatically destroyed the container in this embodiment. The alcohol was subsequently released in the submitted dimethylformamide and dissolved. Afterwards gave the experimenter add a 1.0 mmol container of sodium hydride (0.024 g, 1.0 mmol, 1.0 eq.) as described above. Since he had to use 1.1 equivalents as described above, another 0.1 mmol container of sodium hydride (0.0024 g, 0.1 mmol, 0.1 eq.) Was added. These containers were also destroyed automatically and the sodium hydride suspended in dimethylformamide. The reaction mixture was heated at 40 ° C. for 15 minutes and then a further 1.0 mmol container of benzyl bromide (0.171 mg, 0.109 ml, 1.0 mmol, 1.0 eq.) Was added at room temperature. The reaction mixture was stirred for 4 hours at room temperature. Subsequently, two 1.0 mmol containers with 10 M HBr _aq (0.1 ml each, 1.0 mmol., With respect to HBr) were successively added to the solution, the reaction mixture was filtered off and the filtrate was evaporated.

Example 2: Synthesis of a substituted aminocyclohexane library by double reductive amination in the key step

The aldehyde building blocks and batch sizes for this example are shown in the following Table 2: Aldehyde and reagent data used for the 1st step X mg reagent Aldehyde and reagent data used for the 2nd step Y mg or μl of reagent 1 3-Benzyloxybenzaldehyde (M = 212.25, 95%) 24.5 mg 2,4-dichlorobenzaldehyde (M = 175.01, 99%) 17.7 mg 2 3-Benzyloxybenzaldehyde (M = 212.25, 95%) 24.5 mg 4-Methoxybenzaldehyde (M = 136.15, d = 1,119, 98%) 12.4 μl 3 3-Benzyloxybenzaldehyde (M = 212.25, 95%) 24.5 mg 4-t-butyloxybenzaldehyde (M = 162.23, d = 0.969, 97%) 17.2 μl 4 3-Benzyloxybenzaldehyde (M = 212.25, 95%) 24.5 mg 4-phenyloxybenzaldehyde (M = 198.22, d = 1,132, 98%) 17.8 μl 5 4-Benzyloxybenzaldehyde (M = 212.25, 97%) 24.0 mg 2,4-dichlorobenzaldehyde (M = 175.01, 99%) 17.7 mg 6 4-Benzyloxybenzaldehyde (M = 212.25, 97%) 24.0 mg 4-Methoxybenzaldehyde (M = 136.15, d = 1,119, 98%) 12.4 μl 7 4-Benzyloxybenzaldehyde (M = 212.25, 97%) 24.0 mg 4-t-butyloxybenzaldehyde (M = 162.23, d = 0.969, 97%) 17.2 μl 8th 4-Benzyloxybenzaldehyde (M = 212.25, 97%) 24.0 mg 4-phenyloxybenzaldehyde (M = 198.22, d = 1,132, 98%) 17.8 μl

a) Classic experiment

• 1st stage: 9.91 mg (0.100 mmol, M = 99.1, 1.00 eq) of aminocyclohexane 1 were dissolved in 1.5 ml of dry THF per reactor. X mg (0.110 mmol, 1.1 eq) of the first aldehyde 2 (3-or 4-benzyloxybenzaldehyde) was added and the reaction mixture was stirred for 10 min. stirred under inert gas at room temperature. Subsequently, 30.2 mg of sodium umtriacetoxyborohydride 3 (0.15 mmol, 1.5 eq) were added and the reaction was stirred for 6 hours under inert gas at room temperature.
• 2nd step: Y mg or μl (0.100 mmol, 1.0 eq) of the second aldehyde 4 and 30.2 mg sodium triacetoxyborohydride 3 (0.15 mmol, 1.5 eq) were added and the reaction mixture was stirred under inert gas at room temperature for 10 h.
• Work-up: The reactions were followed by TLC (petroleum ether / ethyl acetate 7: 3), then evaporated to dryness and used directly in the next step without further purification.

b) New procedure with reagent containers

• 1st stage: 1.5 ml of dry THF were initially charged per reactor. Under intense stirring, a 0.100 mmol container (9.91 mg, 1.00 eq) of aminocyclohexane 1 was added. The intense stirring causes in all cases of a container addition, the release of the reagent from the container, in this case by irreversible destruction of the glass container. A 0.100 mmol and a 0.010 mmol container (total X mg, 1.1 eq) of the first aldehyde 2 (3- or 4-benzyloxybenzaldehyde) were added to the reactor with stirring. After 10 min. A 0.100 mmol and a 0.050 mmol container sodium triacetoxyborohydride 3 (total 30.2 mg, 1.5 eq) were added to the reactor and stirred vigorously under inert gas at room temperature for 6 h.
• 2nd stage: A 0.100 mmol container (Y mg or μl, 1.0 eq) of the second aldehyde 4 and a 0.100 mmol and a 0.050 mmol container of sodium triacetoxyborohydride 3 (total 30.2 mg, 1.5 eq) were added to the reactor thereafter and the reagents were released from the containers by vigorous stirring. The reaction mixture was stirred under inert gas at room temperature for 10 hours.
• Work-up: The reactions were followed by TLC (petroleum ether / ethyl acetate 7: 3), filtered (removal of the container residues), then evaporated to dryness and used directly in the next step without further purification.

Example 3: Preparation of α, β-unsaturated Enones by Horner-Emmons Reaction

The building blocks and batch sizes for this example are shown in the following Table 3: Aldehyde and reagent data X mg added reagent Phosphonate and reagent data Y mg or μl of reagent Base and reagent data Z mg or μl of reagent 1 Naphthaldehyde (M = 156.19, 97%) 1,610 g Dimethylacetyl methyl phosphonate (M = 166.12, d = 1,202, 97%) 1.57 ml NaH (M = 24.00, 55%) 436 mg 2 Naphthaldehyde (M = 156.19, 97%) 1,610 g Dimethylacetyl methyl phosphonate (M = 166.12, d = 1,202, 97%) 1.57 ml BuLi (10M in hexane) 1.0 ml 3 Naphthaldehyde (M = 156.19, 97%) 1,610 g Diethyl (1-cyanoethyl) phosphonate (M = 191.17, d = 1,085, 98%) 1.98 ml NaH (M = 24.00, 55%) 436 mg 4 Naphthaldehyde (M = 156.19, 97%) 1,610 g Diethyl (1-cyanoethyl) phosphonate (M = 191.17, d = 1,085, 98%) 1.98 ml BuLi (10M in hexane) 1.0 ml 5 o-tolualdehyde (M = 120.15, d = 1039, 97%) 1.19 ml Dimethylacetyl methyl phosphonate (M = 166.12, d = 1,202, 97%) 1.57 ml NaH (M = 24.00, 55%) 436 mg 6 o-tolualdehyde (M = 120.15, d = 1039, 97%) 1.19 ml Dimethylacetyl methyl phosphonate (M = 166.12, d = 1,202, 97%) 1.57 ml BuLi (10M in hexane) 1.0 ml 7 o-tolualdehyde (M = 120.15, d = 1039, 97%) 1.19 ml Diethyl (1-cyanoethyl) phosphonate (M = 191.17, d = 1,085, 98%) 1.98 ml NaH (M = 24.00, 55%) 436 mg 8th o-tolualdehyde (M = 120.15, d = 1039, 97%) 1.19 ml Diethyl (1-cyanoethyl) phosphonate (M = 191.17, d = 1,085, 98%) 1.92 ml BuLi (10M in hexane) 1.0 ml

a) Classic experiment

Y ml of phosphonate 2 (11.0 mmol, 1.1 eq) was dissolved in 50 ml of dry THF under inert gas. 436 mg NaH 3 or 1.0 ml of BuLi 3 '(10.0 mmol, 1.0 eq) were added to this solution with stirring. After 3 min at room temperature, aldehyde 1 (10.0 mmol, 1.0 eq) was added and the reaction mixture was stirred at 55 ° C for 4 h.

Work up: The reaction was followed by TLC (petroleum ether / ethyl acetate 8: 2) and then evaporated to dryness. It was then extracted with DCM (20 ml) and water (20 ml), the organic phase was washed with sat. NaCl solution (20 ml) and dried over sodium sulfate. Further purification of the product was carried out by means of flash chromatography (ether / ethyl acetate 9: 1, then 8: 2).

b) New procedure with reagent containers

In a reactor, 50 ml of dry THF were placed under inert gas. A 10.0 mmol and a 1.0 mmol container of phosphonate 2 (total Y mg or ml, 1.1 eq) were added to the reactor with vigorous stirring. The intense stirring in all cases of container addition causes the release of the reagent from the container, in this case by irreversible destruction of the glass container. Subsequently, a 10.0 mmol container of base 3 or 3 ' (total: Z mg or ml, 1.0 eq) was added to the reactor. 3 min after this addition, a 10.0 mmol container was added with aldehyde 1 . The reaction mixture was stirred at 55 ° C for 4 h.

Work-up: The reaction was followed by TLC (petroleum ether / ethyl acetate 8: 2), then filtered (removal of the container residues) and then evaporated to dryness. It was then extracted with DCM (20 ml) and water (20 ml), the organic phase was washed with sat. NaCl solution (20 ml) and dried over sodium sulfate. Further purification of the product was carried out by means of flash chromatography (ether / ethyl acetate 9: 1, then 8: 2).

The result obtained was in every way comparable to the extremely careful classical reaction, ie without the use of containers.

Table 4 below lists a set of 10 substances which have been packed airtight in 3 different mmol amounts in glass containers according to FIG. 1. This system of containers has practically the same advantage in usability as that described in Table 1. Thus, for example, a reaction with one equivalent of a first substance (eg 1 container of the third column) and 1.1 equivalents of a second substance (1 container of the second and third columns) can be carried out. No substance Amount of substance in a container with respect to mmol 1 Benzyl bromide, C ₇ H ₇ Br, 99% 0011 00:11 1.11 2 Sodium hydride, NaH, 55-60% 0011 00:11 1.11 3 Cyclohexanol C ₆ H ₁₂ O, 98% 0011 00:11 1.11 4 48% HBr _aa (mmol relative to HBr) 0011 00:11 1.11 5 Dimethylformamide, C ₃ H ₇ NO, 99.5%, 0011 00:11 1.11 6 Sodium borohydride, NaBH ₄ , 96% 0011 00:11 1.11 7 Lithium aluminum hydride, LiAlH ₄ , 97% 0011 00:11 1.11 8th Boron tribromide, BBr ₃ , 99% 0011 00:11 1.11 9 Boron trifluoride ethyl etherate BF ₃ Et ₂ O 0011 00:11 1.11 10 Butyllithium solution, C ₄ H ₉ Li-10M in hexane 0011 00:11 1.11

In addition to glass containers, other containers were tested. The application principle is virtually identical. The containers are made of an optimally inert (compared to glass usually less widely used) plastic. Especially in applications where e.g. Cell cultures can be used, other materials may be beneficial because the glass residues (container residues) can damage the cells. The results are comparable. The containers are not broken as described in the case of the glass containers (completely or via a predetermined breaking point). With an adhesive (as small as possible), after filling the substance under inert conditions, a lid is applied which dissolves by the action of a solvent or by physical forces (e.g., strong stirring or ultrasonication), thus releasing the corresponding substance.

With the inventive solution with containers of different substances with different contents in terms of the number of moles chemical reactions can be very simple, safe, clean, etc. performed by one, two, three, four or more containers in a predetermined order by the experimenter and under certain Conditions by hand, a tool, a robot, etc. are placed in a reaction vessel and the substances after release from the containers (can also be done shortly before, during or after the addition of the container in the reaction vessel) mix and / or react with each other, etc .. If the containers are made of eg thin glass, they are broken in the course of the addition or shortly thereafter. In this case, one or more substances can be added classically, but at least one substance can be added to the described container in the manner described. The glass residues can be used shortly before or during the addition, eg through a filter (for liquids) or but only during or even after the reaction in any way (eg filtration, removal of magnetized container residues with a magnetic field, etc.) are removed. Since, for example, glass is inert to the vast majority of substances or physical conditions used in chemical or biochemical research, in most cases it leaves all the possibilities described open and it is up to the user to decide when and, if at all, if he or she chooses the container remains removed. In many cases, in particular in the area of chemical development or process development, it may even be of advantage (with regard to expenditure, etc.) that the container residues, especially in the case of glass, are not removed at all. In other cases, these can be removed, for example, only after the reaction, for example during the work-up of the reaction mixture, after the work-up of the reaction mixture, etc. This saves not only the disposal of the possibly contaminated container remains (potential health hazards, potential environmental hazards, etc.), but saves the experimenter the most expensive removal, the use of a possibly expensive tool, etc. The container remains are not then removed, for example, if the experimenter only interested in the process data and not in the product. The container residues can then be disposed of either together with the reaction medium (in this case the product) or with the work-up residue. This also has the advantage that the experimenter does not often have to dispose of hazardous contaminated container residues in various ways, but only a uniform mixture (product mixture or reprocessing mixture with container residues).

Ideally, all containers are in the widest possible millimolar range, each filled with those commonly used in chemical or biochemical research Substances equal to or equal in size in at least two dimensions. This has the advantage that all containers of substances with a wide variety of quantities with respect to mmol are stored the same and above all by eg a robot for storage or synthesis itself can be handled the same and eg the reaction vessel openings and others for storage and / or synthesis necessary installations can be dimensioned according to simple.

The substances are, as mentioned, usually used in a certain ratio in terms of number of atoms or molecules. The inventive system thus corresponds to a "millimolization" of chemistry. The units used are usually mol or milimol and no longer as usual today in the described application kilogram or liter. This is crucial to make the overall system compatible and efficient.

As many as possible of the substances used in chemical research and development are to be advantageously available to the experimenter in containers according to the invention in such a way that they do not differ in terms of the absolute amount to be metered, expressed in terms of the number of atoms, molecules or complexes, etc. limited, if necessary, using a plurality of containers for the same substance. That is, if a particular substance is present, for example, at least in the amount 10 ^-4 mol, but advantageously in two, three, four, etc. different, useful for the potential applications in chemical research orders of magnitude, it may at most a variety of containers are metered to 10 ^-4 mol exactly. Advantageously, the other substances used in the same or different chemical reactions are present in the same number of moles in at least one similar container. The same The number of moles or at least a factorial number of moles is necessary for a well-functioning system, the similar containers not only facilitate the manual work, but allow a more easily implemented automation or semi-automation.

For example, the experimenter may perform a chemical reaction in which, for example, he needs to mix 10 ^-3 moles of a substance A with 1.1 equivalents of a substance B by filling 10 containers each with 10 ^-4 moles of substance A and 11 containers each filled with 10 ^-4 mol of the substance B brings together and the substances are released as described above either shortly before the addition of the container, during the addition of the container or in the reaction vessel itself in the manner described above.

Advantageously, in a further gradation should be such that the experimenter at a relative to the amount of substance in the container large amount can change to a next higher container unit. Thus, the number of containers per reaction can be reduced to a minimum. The example described above then looks like that it contains 1 container filled with 10 ^-3 mol of the substance A with a container filled with 10 ^-3 mol of the substance B and a container filled with 10 ^-4 mol of the substance B in the manner described brings together and performs the reaction.

Claims (36)

1. A method for carrying out a chemical reaction between at least a first substance and a second substance, in which a premetered amount of the first substance and a premetered amount of the second substance which is the molar equivalent of the premetered amount of the first substance or is graduated thereto based on mole equivalents are used, characterized in that a first premetered amount of the first substance is present in a first container, which is sealed air-tight, and a second premetered amount of the first substance which is the molar equivalent of the first premetered amount of the first substance or is graduated thereto based on mole equivalents is present in a second container, which is sealed air-tight, and the first and second premetered amounts of the first substance are substantially completely released from said containers and are substantially completely used in the reaction.
2. The method as claimed in claim 1, characterized in that at least two reactions, preferably a multiplicity of reactions, are carried out in parallel, in each of which at least one container which is sealed air-tight and contains in each case a premetered amount of a substance which is released from said container is used.
3. The method as claimed in claim 2, characterized in that the reactions differ in at least one respect, either in the reaction conditions or in one of the substances used, in particular the amount thereof.
4. The method as claimed in any of claims 1 to 3, characterized in that at least two of the substances are each present in at least one container which is sealed air-tight and contains in each case a premetered amount of a substance, which substances are substantially completely released from said containers and are used in the reaction.
5. The method as claimed in any of claims 1 to 4, characterized in that it is a chemical or biochemical synthesis method, preferably for the preparation of a product or product mixture to be investigated.
6. The method as claimed in claim 5, characterized in that a product is prepared that is no bioorganic polymer, preferably no polymer at all.
7. The method as claimed in any of claims 1 to 6, characterized in that at least one of the substances is released by at least partial, preferably irreversible, elimination of the air-tight seal of the at least one container, directly where the reaction takes place.
8. The method as claimed in any of claims 1 to 7, characterized in that at least one of the substances is released by at least partial, preferably irreversible, elimination of the air-tight seal of the at least one container and then added to the at least one further substance.
9. The method as claimed in claim 7 or 8, characterized in that the at least partial elimination of the air-tight seal of the at least one container is effected by nontargeted use of a chemical, physical or mechanical effect.
10. The method as claimed in any of claims 1 to 9, characterized in that the premetered amount is 1, 2, 5, 10, 20, 50, 100, 200, 500, 1 000, 2 000, 5 000, 10 000, 20 000, 50 000, 100 000, 200 000, 500 000, 1 000 000, 2 000 000, 5 000 000, 10 000 000, 20 000 000, 50 000 000 or 1 000 000 000 nmol, preferably 1, 2, 5, 10, 20, 50, 100, 200, 500, 1 000, 2 000, 5 000, 10 000, 20 000, 50 000, 100 000, 200 000, 500 000, 1 000 000, 2 000 000, 5 000 000 or 10 000 000 nmol.
11. The method as claimed in any of claims 1 to 10, characterized in that at least one third container with a premetered amount of the second substance which is the molar equivalent of the premetered amount of the first substance or is graduated thereto based on mole equivalents is used.
12. The method as claimed in any of claims 1 to 11, characterized in that the second container comprises a second premetered amount of the first substance which is graduated relative to the first premetered amount of the first substance based on mole equivalents.
13. The method as claimed in claim 12, characterized in that the second premetered amount of the first substance is an integral multiple of the first premetered amount of the first substance.
14. The method as claimed in any of claims 11 to 13, characterized in that at least one fourth container with a premetered amount of the second substance which is graduated relative to the premetered amount of the second substance in the third container based on mole equivalents is at least also used.
15. The method as claimed in any of claims 11 to 14, characterized in that at least one further container with a premetered amount of a third substance which is the molar equivalent of the premetered amount of the first substance or is graduated thereto based on mole equivalents is used.
16. The method as claimed in any of claims 11 to 15, characterized in that the first container has x nmol of substance and the at least one third container y·x/1 000 nmol of substance, where x and y are integers and y is preferably a number from 1 001 to 1 000 000, more preferably from 1 010 to 100 000, more preferably from 1 100 to 10 000.
17. The method as claimed in any of claims 1 to 16, characterized in that at least three containers with different substances are used.
18. A set of containers containing substances, characterized in that it comprises at least one first container with a first premetered amount of a first substance, at least one second container with a second premetered amount of the first substance which is graduated relative to the first premetered amount based on mole equivalents, at least one third container with a premetered amount of a second substance which is the molar equivalent of the first premetered amount of the first substance, and at least one fourth container with a premetered amount of the second substance which is graduated relative to the first premetered amount of the second substance in the third container based on mole equivalents.
19. The set as claimed in claim 18, characterized in that the premetered amounts of further substances in further containers are in each case molar equivalent amounts of the premetered amount of the first substance in the first container, or integral multiples thereof.
20. The set as claimed in claim 18 or 19, characterized in that at least one of the substances is a pure chemical compound, preferably both substances are pure chemical compounds.
21. The set as claimed in any of claims 18 to 20, characterized in that the at least one first container contains x nmol of the first substance and the at least one second container y·x/1 000 nmol of the first substance, where x and y are integers and y is preferably a number from 1 001 to 1 000 000.
22. The set as claimed in claim 21, characterized in that y is 2 000, 3 000, 4 000, 5 000, 6 000, 7 000, 8 000, 9 000 or 10 000, preferably 2 000, 5 000 or 10 000, more preferably 5 000 or 10 000.
23. The set as claimed in claim 21 or 22, characterized in that x is 1, 2, 5, 10, 20, 50, 100, 200, 500, 1 000, 2 000, 5 000, 10 000, 20 000, 50 000, 100 000, 200 000, 500 000, 1 000 ,000, 2 000 000, 5 000 000, 10 000 000, 20 000 000, 50 000 000 or 1 000 000 000, preferably 1, 2, 5, 10, 20, 50, 100, 200, 500, 1 000, 2 000, 5 000, 10 000, 20 000, 50 000, 100 000, 200 000, 500 000, 1 000 000, 2 000 000, 5 000 000 or 10 000 000, more preferably 1, 10, 100, 1 000, 10 000, 100 000, 1 000 000 or 10 000 000, more preferably 1, 10, 100, 1 000, 10 000, 100 000 or 1 000 000.
24. The set as claimed in any of claims 18 to 23, characterized in that it comprises at least three, preferably at least 5, more preferably at least 10, more preferably at least 100, more preferably at least 1 000, containers with different substances.
25. The set as claimed in claim 24, characterized in that it comprises in addition to the containers with different substances in each case at least one, preferably at least three, more preferably at least five, further containers with the same substance in amounts graduated relative to the first premetered amount of the respective substance based on mole equivalents.
26. The set as claimed in any of claims 18 to 25, characterized in that at least one, preferably each, of the containers does not contain a molar solution.
27. The set as claimed in any of claims 18 to 26, characterized in that, in the containers, any space not filled with the substance is substantially completely filled with a gas, a mixture of gases or a liquid, which gas, mixture or liquid contains less than 5%, preferably less than 1%, preferably less than 0.1%, of O₂.
28. The set as claimed in any of claims 18 to 27, characterized in that, in the containers, the space not filled with substance is substantially completely filled with an inert gas, preferably N₂, SF₆, a chlorofluorocarbon or a noble gas, in particular Ar, Ne, Xe or He.
29. The set as claimed in any of claims 18 to 28, characterized in that the substance in at least one of the containers is a catalyst, inhibitor, initiator or an accelerator.
30. The set as claimed in any of claims 18 to 29, characterized in that the containers are sealed air-tight, the air-tight seal of the containers being capable of being at least partly eliminated, preferably irreversibly.
31. The set as claimed in any of claims 18 to 30, characterized in that the containers have a container wall thickness of from 0.0001 mm to 5 mm, preferably from 0.0001 mm to 3 mm, more preferably from 0.0001 mm to 2 mm, more preferably from 0.001 mm to 2 mm, more preferably from 0.001 mm to 1 mm, more preferably from 0.01 mm to 1 mm, more preferably from 0.02 mm to 1 mm, more preferably from 0.02 mm to 0.5 mm, more preferably from 0.02 mm to 0.3 mm.
32. The set as claimed in any of claims 18 to 31, characterized in that the largest diameter of the containers are of the same magnitude.
33. The set as claimed in any of claims 18 to 32, characterized in that the containers are provided with a substance designation and/or quantity specification, preferably by means of a code, in particular a bar code, the substance designation and/or quantity specification preferably being scored into the containers.
34. The set as claimed in any of claims 18 to 33, characterized in that a plurality of containers is arranged in a matrix which, for carrying out a plurality of chemical reactions, can be mounted directly on a matrix of reaction vessels or an automatic laboratory apparatus, the containers in the matrix being capable of being transported individually, together or group by group into the reaction vessels.
35. The set as claimed in any of claims 18 to 34, characterized in that at least one of the substances is a mixture of characterized chemical compounds, in particular a mixture of not more than four pure chemical compounds, in particular a mixture of not more than four pure chemical compounds in solution or suspension.
36. The use of a set as claimed in any of claims 18 to 35 for carrying out the method as claimed in any of claims 1 to 17.

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