US2646432A - Method of preparing 2, 6-diketopurines - Google Patents

Method of preparing 2, 6-diketopurines Download PDF

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US2646432A
US2646432A US721883A US72188347A US2646432A US 2646432 A US2646432 A US 2646432A US 721883 A US721883 A US 721883A US 72188347 A US72188347 A US 72188347A US 2646432 A US2646432 A US 2646432A
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US721883A
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August H Homeyer
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Mallinckrodt Chemical Works
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline

Definitions

  • This invention relates to nitroso compounds and more particularly tothe reduction of nitroso compounds.
  • the .invention accordingly comprises- .;the
  • the reaction may be convenientlyca'rried'out at. atmospheric pressures, although if desired elevated pressures may b'e'employed. They are not essential for carrying-out the reaction.
  • the hydrogen obtained as bythe cracking of-am- The hydrogen maybe diluted With inert gases, suchas nitrogen, Without interfering with the reaction. Accordingly, mixtures of nitrogen and monia may be utilized for this purpose.
  • The' formyl compound may thenbe used in the customary manner for the preparation 'of theo- 'phylline.
  • the reduced compound is not only obj tained'economically and in high yield, but the product of. the present process is substantially .free of salts and other impurities which would have .been' introduced by customary reduction Y methods.
  • While Water'constitutes the preferred suspend- .ing medium, other inert substances maylikewise correspondingudiamino: compound may be c'a'r- -' be present.
  • the reaction may be carried out under acid or alkaline conditions; e. g'., Where an acid such as formic acid or acetic acid is used, oran alkaline reagent suchas ammonia. If the catalyst employed is acidsoluble, the proportion of the" acid and its concentration should not be such as to destroy the activity of the catalyst.
  • the hydrogen inlet- was attached to a supply of hydrogen at atmospheric pressur in a gasom- -;--;:eter.
  • the flask was charged with 1,3-dimethyl 4-;amino-5Fnitrcsouracilmonohydrate (5 5 g., 0.27
  • the flask contained a suspension of 4,5-diaminouracil.
  • warming and the nickel catalyst may be separated by decantation or filtration.
  • the catalyst usually retains its activity and can be reused.
  • the solution of diamino compound after separation of the nickel catalyst, was acidified with 30 ml. of 87% formic acid and heated at 90-95" C. for 30 minutes.
  • the solution now contained .the formyl derivative of l ,3-dimethyl-4,5-diaminouracil which crystallizes on cooling the solution and may be recovered.
  • the hot solution of th formyl derivative was neutralized to phenolphthalein indicator by adding 40 ml. of MN sodium hydroxide solution and then an excess of 45 ml. more of the alkali was added.
  • the strongly alkaline solution was heated at 90 C. for minutes to convert the formyl compound 'to theophylline.
  • the solution was acidified with sulfuric acid and allowed to cool; theophylline separated in crystalline form.
  • Example 2 A flask of 500 ml. capacity arranged on a shaking machine for catalytic hydrogenation was charged with water (200 ml.), 1,3-dimethyl-4- amino-S-nitrosouracil (10 g.), acetic acid ml), palladium chloride (3 ml. of 1% solution) and gum arabic (3 ml. of 1% solution). The flask was flushed out with hydrogen from a gasometer at atmospheric pressure and shaken at room temperature. hydrogen was absorbed during seven hours. The red color of the nitroso compound had disappeared and the solution contained 1,3-dimethyl- 4,5-diaminouracil in high yield as shown by its conversion to theophylline as described in Example 1.
  • Example 4 l-amino-fi-nitrosouracil (1.75 g.) suspended in water (40 ml.) was reduced in the apparatus describedin Example 3.
  • the catalyst was platinum dioxide (0.1 g.).
  • a total of 470 ml. of hydrogen was absorbed in two hours and the red color of A total of 2550 ml. of
  • solution contained 1,3-dimethyl-4,5-diaminouraoil in high yield.
  • Example 6 Anapparatus similar to that described in Example 3 was charged with 1,3-dimethyl-4-amino- 5-nitrosouraci1 (6 g.), water (40 ml), concentrated ammonia (5 ml.), and nickel catalyst (l g.). The flask was flushed with hydrogen and shaken at room temperature. Hydrogen was absorbed and the red color of the nitroso compound disappeared. The reduction was complete in three hours, the solution containing the l,3dimethyl-4,5-diaminouracil product.
  • Example 7 Th procedure described in Example 7 was repeated except that the concentrated ammonia was omitted from the reagents and 5 ml. of glacial acetic acid was added. The reduction proceeded with absorption of hydrogen and disappearance of the red color of the nitroso compound. When the reduction was complete the solution contained 1,3-dimethyl-4,5-diaminouracil. Y
  • the reduction of a"4-amino-5-nitrosouracil can be carried out at ordinary temperature and pressure by hydrogen and a reducing catalyst such as nickel, palladium or platinum.
  • Nickel is the preferred catalyst.
  • catalyst should be suspended in an inert medium such as water or alcohol and the agitation or shaking must be sufiiciently vigorous to give a very fine dispersion of the hydrogen in the inert medium.
  • High pressures may be used.
  • the hydrogen may be diluted with inert gases such as nitrogen, from cracked ammonia for example, without interfering with the reaction but provision must'be made for suitable elimination of the diluent.
  • the reaction may be conducted over a wide range of temperatures but for best results it is generally preferred tooperate below C.
  • the solution of the dimethyl cliaminouracil is well adapted for conversion to the formyl derivative which can be easily accomplished by the addition of formic acid and heating.
  • the advantage of using a catalytic reduction is its economy of materials and production of the product, obtained in high yield, in a solution free of salts or other impurities.
  • the reduction is conveniently carried out using water asa suspending medium but it is possible amount and concentration of acid should not be such as to dissolve the metal.
  • the method of reducing the nitroso group of 1,3-dimethyl-4-amino-5-nitrosouraci1 to convert the nitroso group to an amino group comprises reacting said compound with hydrogen at a temperature not substantially in excess of 85 C. and in the presence of a catalyst containing at least one metal selected from the group consisting of nickel, palladium and platinum.
  • the method which comprises reacting a 4-amino-5-nitrosouracil with hydrogen at a temperature not substantially in excess of 85 C. and in the presence of a catalyst selected from the group consisting of nickel, palladium and platinum to form a 4,5-diaminouracil, formylating the product by reaction with formic acid, and cyclizing the formylated compound with an alkali to form a purine, said formylation and cyclizing being carried out without isolation of intermediates.

Description

indicated in the-following claims. i In accordance-with the-present invention; it -has been foundthatnitrosorcompounds of'the Patented July 21, 1953 -.-'METHOD 0F PREPARING ,ae-DI EroPURINEs August HF- HOmeyer, Webster Groves, Mo., as signer to Mallinckrodt 'Cheinical' Works, St.
Louis, Mo., a. corporaticnnfltllfissouri .-.-,N jy]) :a,wing.:1-Application Januaryi.i3',"19.47,
..-:Serial No..'Z21,883
This invention relates to nitroso compounds and more particularly tothe reduction of nitroso compounds.
Among the 'objects of thisinvention are the; provision of methods for the reduction of nitroso compounds; the provision'of methods of the type referred to in which thereduction is carried out catalytically; the provision of methods. of the type referred to in whichthe reduction is easily and quickly carried out at-relativelylow cost} and the provision of methods of the type indicated in whichthe resulting reduced product is particularly-adapted for subsequent processing. Other objects will .be inpart apparent and in .part pointedout hereinafter. 1
The .invention accordingly comprises- .;the
. steps and sequence of-lsteps and ieatures-of'synthesis; analysis,'orsmetathesis, which-will be ex- 1 empllfied in the processes .hereinafter; described,
and the scope-of the application ofwhich Will-be type of 4- amino-Smitrosouracil can:be-reduced. catalytically with hydrogen gas. Thereduction is easily carried out with recovery of substan- .ntially all. of. the catalytic material employed if Y desired. Amongthe catalysts which have been found effective for-thisreactionare nickel, pal- I ladium.andplatinum.- It is preferred that the catalyst be in a state of relativelyfine subdivision.
-The process of'the presentjrinvention may be illustrated by 1 the catalytic reduction :of 21-,3'-pdi- .methyl-4::amino-S-nitrosouracil:
- The present process; however, is also'applicable to the reduction" "of the 'c'orrespondingz..nitroso= compounds having *aisinglemethyl' group in: either the one or three position:or in 'which both positions contain no substituents.
The reduction of the "nitroso' comp'ound to: the
ried out at ordinary temperatures :and pressures merely by reducingithe. nitroso compound: in a mixture containing the catalystisuspended 'in an 1 Claims. (oizfzeo-i-zse) 1 pera'tures maybe used ifdesired, although,since this isnot necessary, it is preferred that the reaction be carried out at approximately room temperature. In general, thereaction temperature shouldnot be permitted to rise substantially above 85 C. However the preferred reaction' conditions under which the best yields have been T obtained 'are temperatures not substantially in excess of 55C; r
The reaction may be convenientlyca'rried'out at. atmospheric pressures, although if desired elevated pressures may b'e'employed. They are not essential for carrying-out the reaction.
hydrogen obtained as bythe cracking of-am- The hydrogen maybe diluted With inert gases, suchas nitrogen, Without interfering with the reaction. Accordingly, mixtures of nitrogen and monia may be utilized for this purpose.
' plished by the formation of the formyl compound After completion of the reaction and removal of the catalyst ..the 'solution of dimethyldiaminouracil is well adapted for conversion to the formyl derivative. This can be easily accomin the usual Way.
.The' formyl compound may thenbe used in the customary manner for the preparation 'of theo- 'phylline. The reduced compound is not only obj tained'economically and in high yield, but the product of. the present process is substantially .free of salts and other impurities which would have .been' introduced by customary reduction Y methods.
While Water'constitutes the preferred suspend- .ing medium, other inert substances maylikewise correspondingudiamino: compound may be c'a'r-=-' be present. The reaction may be carried out under acid or alkaline conditions; e. g'., Where an acid such as formic acid or acetic acid is used, oran alkaline reagent suchas ammonia. If the catalyst employed is acidsoluble, the proportion of the" acid and its concentration should not be such as to destroy the activity of the catalyst.
The following examples illustrate the invention:
. I .Escamplel Acne-liter,rthree-necked'flask was fittedwith a' mechanical stirrer, hydrogen inlet-tube and thermometer. The stirrer Was apiece of stainless inert medium such'asivvater on alc'ohol.= This suspension should" be agitated sufli'ciently :vigor ously: to "give a very finefidispersion "ofihydrogen .a in: the inert medium;- Alternatively; other methods may be adoptediwhi'chzprovide a iine disp'er- 'sion .of the; gaseous p'articles: of -the' hydrogen 1 throughout 1 thereaction:- mixture. Higher zt'em steel Wire one-sixteenth inch in diameter attached in a loop about three inches across to a A; inch diameter shaft fitted. with a gas-tight stufiingibox and driven at high speed "by a motor.
The hydrogen inlet-was attached to a supply of hydrogen at atmospheric pressur in a gasom- -;--;:eter. The flask was charged with 1,3-dimethyl 4-;amino-5Fnitrcsouracilmonohydrate (5 5 g., 0.27
the nitroso compound disappeared. The flask contained a suspension of 4,5-diaminouracil.
Example 1,3-dimethyll-amino-5 nitrosouracil (2 g.). alcohol (40 ml.), and nickel catalyst (0.3 g.)
were placed in a flask and shaken with hydrogen at room temperature and atmosphericpressure as described in Example 3. A total of 580 ml. of
hydrogen was absorbed in two hours and the red color of th nitroso compound disappeared. The
warming and the nickel catalyst may be separated by decantation or filtration. The catalyst usually retains its activity and can be reused.
The solution of diamino compound, after separation of the nickel catalyst, was acidified with 30 ml. of 87% formic acid and heated at 90-95" C. for 30 minutes. The solution now contained .the formyl derivative of l ,3-dimethyl-4,5-diaminouracil which crystallizes on cooling the solution and may be recovered.
The hot solution of th formyl derivative was neutralized to phenolphthalein indicator by adding 40 ml. of MN sodium hydroxide solution and then an excess of 45 ml. more of the alkali was added. The strongly alkaline solution was heated at 90 C. for minutes to convert the formyl compound 'to theophylline. The solution was acidified with sulfuric acid and allowed to cool; theophylline separated in crystalline form. The
' first crop weighed 36.4 g. A second crop amounting to.5.2 g. was obtained-by saturating the solution with sodium sulfate. The crude product was recrystallized from water giving 40.8 g. of pure theophylline amounting to 29% of the theoretical yield based on the 1,3-dimethyl-4-an1ino-5- nitrosouracil used as starting material.
Example 2 A flask of 500 ml. capacity arranged on a shaking machine for catalytic hydrogenation was charged with water (200 ml.), 1,3-dimethyl-4- amino-S-nitrosouracil (10 g.), acetic acid ml), palladium chloride (3 ml. of 1% solution) and gum arabic (3 ml. of 1% solution). The flask was flushed out with hydrogen from a gasometer at atmospheric pressure and shaken at room temperature. hydrogen was absorbed during seven hours. The red color of the nitroso compound had disappeared and the solution contained 1,3-dimethyl- 4,5-diaminouracil in high yield as shown by its conversion to theophylline as described in Example 1.
Example 3 .An apparatus similar to that described in Example 2 was used except that the flask was of 125 ml. capacity. l,3-dimethyl-i-amino-5-nitrosoura-cil (2 g), water (40 ml.), and platinum dioxide catalyst (0.1 g.) were placed in the flask and shaken with hydrogen at room temperature and atmospheric pressure. hydrogen was absorbed in two hours and the red color of the nitroso compound disappeared. The solution contained l,3-dimethyl-4=,5-diaminouracil in high yield.
Example 4 l-amino-fi-nitrosouracil (1.75 g.) suspended in water (40 ml.) was reduced in the apparatus describedin Example 3. The catalyst was platinum dioxide (0.1 g.). A total of 470 ml. of hydrogen was absorbed in two hours and the red color of A total of 2550 ml. of
A total-of 495 ml. of
solution contained 1,3-dimethyl-4,5-diaminouraoil in high yield.
Example 6 Anapparatus similar to that described in Example 3 was charged with 1,3-dimethyl-4-amino- 5-nitrosouraci1 (6 g.), water (40 ml), concentrated ammonia (5 ml.), and nickel catalyst (l g.). The flask was flushed with hydrogen and shaken at room temperature. Hydrogen was absorbed and the red color of the nitroso compound disappeared. The reduction was complete in three hours, the solution containing the l,3dimethyl-4,5-diaminouracil product.
Example 7 Th procedure described in Example 7 was repeated except that the concentrated ammonia was omitted from the reagents and 5 ml. of glacial acetic acid was added. The reduction proceeded with absorption of hydrogen and disappearance of the red color of the nitroso compound. When the reduction was complete the solution contained 1,3-dimethyl-4,5-diaminouracil. Y
The reduction of a"4-amino-5-nitrosouracil can be carried out at ordinary temperature and pressure by hydrogen and a reducing catalyst such as nickel, palladium or platinum. Nickel is the preferred catalyst. and catalyst should be suspended in an inert medium such as water or alcohol and the agitation or shaking must be sufiiciently vigorous to give a very fine dispersion of the hydrogen in the inert medium. High pressures may be used. The hydrogen may be diluted with inert gases such as nitrogen, from cracked ammonia for example, without interfering with the reaction but provision must'be made for suitable elimination of the diluent. The reaction may be conducted over a wide range of temperatures but for best results it is generally preferred tooperate below C.
After completion of the reaction and removal of the catalyst the solution of the dimethyl cliaminouracil is well adapted for conversion to the formyl derivative which can be easily accomplished by the addition of formic acid and heating. The advantage of using a catalytic reduction is its economy of materials and production of the product, obtained in high yield, in a solution free of salts or other impurities.
The reduction is conveniently carried out using water asa suspending medium but it is possible amount and concentration of acid should not be such as to dissolve the metal.
In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.
' As many changes could be made in the above processes without departing from the scope of the invention, it is intended that all matter contained' in the above description shall be interpreted as illustrative and not in a limiting sense.
The nitroso compound 1 claim:
1. The method of reducing a 4-amino-5-nitrosouracil to a 4,5 diaminouracil which comprises reacting said nitroso compound with hydrogen at a temperature not substantially in excess of 85 C. and in the presence of a catalyst selected from a group consisting of nickel, palladium and platinum.
2. The method of reducing a 4-amino-5-nitrosouracil to a 4,5 diaminouracil which comprises reacting said nitroso compound with hydrogen at a, temperature not substantially in excess of 85 C. and in the presence of a nickel catalyst. v
3. The method of reducing a 4-amino-5-nitrosouracil to a 4,5 diaminouracil which comprises reacting said nitroso compound with hydrogen at a temperature not substantially in excess of 85 C. and in the presence of a palladium catalyst.
4. The method of reducing a 4-amino-5-nitrosouracil to a 4,5 diaminouracil which comprises reacting said nitroso compound with hydrogen at a temperature not substantially in excess of 85 C. and in the presence of a platinum catalyst.
5. The method of reducing the nitroso group of 1,3-dimethyl-4-amino-5-nitrosouraci1 to convert the nitroso group to an amino group which comprises reacting said compound with hydrogen at a temperature not substantially in excess of 85 C. and in the presence of a catalyst containing at least one metal selected from the group consisting of nickel, palladium and platinum.
6. The method which comprises reacting a 4-amino-5-nitrosouracil with hydrogen at a temperature not substantially in excess of 85 C. and in the presence of a catalyst selected from the group consisting of nickel, palladium and platinum to form a 4,5-diaminouracil, formylating the product by reaction with formic acid, and cyclizing the formylated compound with an alkali to form a purine, said formylation and cyclizing being carried out without isolation of intermediates.
AUGUST I-I. HOMEYER.
References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 716,994 Engelmann Dec. 30, 1902 2,447,523 Mozingo et al Aug. 24, 1948 FOREIGN PATENTS Number Country Date 161,493 Germany Mar. 3, 1904 OTHER REFERENCES Paal et a1., Ber. Deut. Chem., 38, 1406 (1905).
Vavon, Bull. Soc. Chim., 41, 1266 (1927).
Houben, Die Methoden Der Organischen Chemie, Dritte Auflage, p. 390, vol. 2.
Sabatier: Catalysis in Organic Chemistry, 1922 edition, p. 564.
Traube: Berichte, vol. 33, no. 3, (1900), pp. 3053-3054.

Claims (1)

  1. 6. THE METHOD WHICH COMPRISES REACTING A 4-AMINO-5-NITROSOURACIL WITH HYDROGEN AT A TEMPERATURE NOT SUBSTANTIALLY IN EXCESS OF 85* C. AND IN THE PRESENCE OF A CATALYST SELECTED FROM THE GROUP CONSISTING OF NICKEL, PALLDIUM AND PLATINUM TO FORM A 4,5-DIAMINOURACIL, FORMYLATING THE PRODUCT BY REACTION WITH FORMIC ACID, AND CYCLIZING THE FORMYLATED COMPOUND WITH AN ALKALI TO FORM A PURINE, SAID FORMYLATION AND CYCLIZING BEING CARRIED OUT WITHOUT ISOLATION OF INTERMEDIATES.
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2781344A (en) * 1953-05-04 1957-02-12 Monsanto Chemicals Formylation of amino-pyrimidines
US2785163A (en) * 1954-04-23 1957-03-12 New York Quinine And Chemical Process for the formylation of a 5-nitrosouracil
US2785162A (en) * 1954-04-23 1957-03-12 New York Quinine And Chemical Process for the formylation of a 5 nitrosouracil
DE1240527B (en) * 1961-08-17 1967-05-18 Dresden Arzneimittel Process for the preparation of theophylline
FR2398064A1 (en) * 1977-07-20 1979-02-16 Lonza Ag NEW PROCESS FOR PREPARING 5,6-DIAMINO-URACIL FROM 5-NITROSO-6-AMINO-URACIL
EP0010531A1 (en) * 1978-10-20 1980-04-30 Aktiebolaget DRACO 3-Alkylxanthines, processes for their preparation and compositions for use in the treatment of chronic obstructive airway disease and cardiac disease
EP0619310A1 (en) * 1993-04-07 1994-10-12 Boehringer Ingelheim Kg Improved process for the preparation of 1,3-dimethyl-4,5-diamino-uracil
CN104744466A (en) * 2014-10-31 2015-07-01 合肥平光制药有限公司 Synthesis method of high-purity theophylline
CN112142738A (en) * 2020-10-13 2020-12-29 石药集团新诺威制药股份有限公司 Preparation method of theobromine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE161493C (en) *
US716994A (en) * 1902-07-10 1902-12-30 Farbenfabriken Elberfeld Co Process of making theophyllin.
US2447523A (en) * 1948-08-24 Catalytic hyi

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE161493C (en) *
US2447523A (en) * 1948-08-24 Catalytic hyi
US716994A (en) * 1902-07-10 1902-12-30 Farbenfabriken Elberfeld Co Process of making theophyllin.

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2781344A (en) * 1953-05-04 1957-02-12 Monsanto Chemicals Formylation of amino-pyrimidines
US2785163A (en) * 1954-04-23 1957-03-12 New York Quinine And Chemical Process for the formylation of a 5-nitrosouracil
US2785162A (en) * 1954-04-23 1957-03-12 New York Quinine And Chemical Process for the formylation of a 5 nitrosouracil
DE1240527B (en) * 1961-08-17 1967-05-18 Dresden Arzneimittel Process for the preparation of theophylline
FR2398064A1 (en) * 1977-07-20 1979-02-16 Lonza Ag NEW PROCESS FOR PREPARING 5,6-DIAMINO-URACIL FROM 5-NITROSO-6-AMINO-URACIL
EP0010531A1 (en) * 1978-10-20 1980-04-30 Aktiebolaget DRACO 3-Alkylxanthines, processes for their preparation and compositions for use in the treatment of chronic obstructive airway disease and cardiac disease
US4548818A (en) * 1978-10-20 1985-10-22 Kjellin Per G Composition and methods for the treatment of chronic obstructive airway disease and cardiac disease using 3-alkylxanthines
EP0619310A1 (en) * 1993-04-07 1994-10-12 Boehringer Ingelheim Kg Improved process for the preparation of 1,3-dimethyl-4,5-diamino-uracil
US5510484A (en) * 1993-04-07 1996-04-23 Boehringer Ingelheim Kg Process for preparing 1,3-dimethy-4,5-diaminouracil
CN104744466A (en) * 2014-10-31 2015-07-01 合肥平光制药有限公司 Synthesis method of high-purity theophylline
CN112142738A (en) * 2020-10-13 2020-12-29 石药集团新诺威制药股份有限公司 Preparation method of theobromine

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