AU620342B2 - Smoking compositions containing a heteroaromatic flavorant-release additive - Google Patents

Description

Declared at.. Ri hmF 1 irgi.nia,.. .U day of. S p.tithB 1. 19 Signed:. Donal P k Patrick O'Brien, President i i "i 1 I I. L:2<I: Australia PATENTS ACT 1952 F20342 Form COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: Complete Specification-Lodged: Accepted: Lapsed: Published: Priority: Related Art: 0000 o 0 oooo 00 0 0 SNpme of Applicant: 0 00 0' 0 0 0 0 00 Address of Applicant: 0 00 0 00 0 00 c o ,"Actual Inventor: 0 00 0000 00 0 Address for Service: TO BE COMPLETED BY APPLICANT PHILIP MORRIS PRODUCTS INC.

3601 Commerce Road, Richmond, VIRGINIA 23234. U.S.A.

Yoram HOUMINER Henry V. SECOR Jeffrey I. SEEMAN CALLINANS Patent Attorneys, of 48-50 Bridge Road, Richmond, State of Victoria, Australia.

00 00 00 0 0 9 Complete Specification for the invention entitled: SMOKING COMPOSITIONS CONTAINING A o° HETEROAROMATIC FLAVORANT-RELEASE ADDITIVE The following statement is a full description of this invention, including the best method of performing it known to me:-* SNote: The description is to be typed in double spacing, pica type face, in an area not exceeding 250 mm in depth and 160 mm in width, on tough white paper of good quality and it is to be inserted inside this form.

-C ri a la I, It t PM 6- 3 SMOKING COMPOSITIONS COI'TATHNIG A HETEROAPOMATIC FLAVOPANT-RELEASE ADDITIVF BACKGROUND OF THE IVENTION It has been establ ished that alkylpyrazines are natural components of tobacco smoke, an(! are contributors to tobacco smoke flavor Raoaet- et a] *Chromatog, 97, 79 (1974) !urther, it ha&: been 6isclosed in the patent I iteratur(- that acddi tion of alkyl Pyrazines to tobacco resul f- in an improvement in the flavor of smoking composih'ons as percoivee hy a tezt panel.

U.S. Pat. No. 3,402,051 describes a process for impartina a popcorn-like flavor and4 aroma to tobacco and foodstuffs by the incorporation of a 0000 (0...e15 2-acetylpyrazine derivative therein.

0.00 Other patents wl-'ich disclose the adldition of 000 various pyrazine compounds to tobacco and foodstuffs 0. a as a means of providinq flavor or flavor enhancement include U.S. Pat. Nos. 3,684,809; 3,705,158; '0020 3,5,3;3,764,349; 3,767,426; and 3,881,025.

U.S. Pat, No. 3,914,227 discloses pyridyl and pyrazy] ketones and their use in altering the o'ranolent-ic proportieF cf tob ,cco an'! foodstuffs, and' 04. U.S. Pat. N o. 4,166,869 discloses acylovrimidinos 253 useful. as f lavorants for the same type of arp J c'at ions.

00Alkylpyridines have als o been found to hie use!ful tobacco additives. As an example, U.S. Pat.

cc cc No. 3,625,224 do!scrihes the use of methylpyri(.1ines, A0 t C 00 C 0 V C ~ilL~il

K;

Sj 2 ethylpyridines and various dialkylpyridines as tobacco additives. U.S. Pat. No. 3,381,691 discloses as a tobacco additive.

It is characteristic of pyridine, pyrazine, pyrinidinr ann other heterocyclic derivatives employed as tobacco flavorants in the prior art, as illustrated by the above described technical literature, that the respectivE, heterocyclic derivatives have the disadvantage of both high volatility and low odor threshold. Both of these properties significantly restrict the extent that these heterocyclic derivatives can be utilized as flavorants in tobacco compositions. A quantity of a pyrazine or pyridine derivative in a tobacco composition sufficient to have a noticeable effect in low deliver.' cigarettes causes a marked pack aroma.

U.S. Pat. No. 4,036,237 endeavors to overcome some of the disadvantaces of the above-described flavorant technology. The said patent provides for 20 the incorporation in smoking compositions of a flavorant compound which imparts cherry-like or fruity flavor to the smoke thereof, which flavorant compound is not lost durina the manufacture and storaae of the flavored smokina composition, and which is readily released when the smokino composition is burncd.

Illustrative of a U.S. Pat. No. 4,036,237 flavo r an compound is ethyl 2,2-dimethyl- 3-hydroxy-3phenylpropionate.

0000 0 0 0000 0000 0oo oo 00 S000 0 0o 0 0 00 0 o 0 e o0 0 00 o0 0 0 00 00 0 0 00 0000 00 0 00 00 0 0 0 0 0 0 0 od -3- U.S. Pat. No. 4,259,969 describes smokinq flavorant-release additives such as 2,3-dihydroxy-2,3-dimethyl-l,4-bis(3,5,6-trimethyl-2 pyrazinyl)butane. Under smoking conditions there are released substituted-pyrazine pyrolysis products which enhance the flavor of the mainstream smoke and improve the aroma of thesidestream sn'oke.

U.S. Pat. No. 4,312,368 and related U.S. Pat.

No. A,479,003 describe heterocyclic-hydroxy-substituted alkanoate flavorant additives such as ethyl 2-(2-butyl)-3-hydroxy-3-methyl-3-(3-pyridy] )propionate:

OP

C-CP-0C CH3 i- 2 CH 3 0000 000 0 .0 00 a 00 0 00 000 00 0 0 0 t0 c 2 Under normal smokinq conditions the flavorant additive pyrolyzes into components which contribute enhanced flavor and aroma to the smoke streams.

U.S. Pat. No. 6,171,214 is of general interest as disclosing pyra7.inp intermediates which are related structurally to the present invention smoking composition additives.

There is continuina research effort to develop~ improved smoking compositions which contain a new and efficient low volatility flavorant-release addi tive, and which genera te r-ai nst ream smoke wi th flavorant-enhanced taste and character under smokingi condi tions.

4 Accordingly, it is an object of this invention to provide smoking compositions havina incorporated therein a flavorant component which is characterized by lack of mobility and/or volatilitv at ambient temperature.

It is another object of this invention to provide smoking compositions having incorporated therein a flavorant-release additive which under normal smokina conditions yields pyrolysis constituents which impart improved flavorant properties to mainstream and sidestream smoke.

It is a further object of this invention to provide novel heteroaromatic compounds of low volatility which are adapted to be incoroorated into ciaarette fillers, and which under normal smokina conditions release volatile alkylpyrazine and other flavorant constituents into ciaarette smoke.

oooO0 Other objects and advantaaes of the present ,ooo invention sha]1 become apparent from the followino 20 description and examples.

Soo o 000 a o o 00 6 a C a i so o I 06

I

1

N

I 1

I

5 DESCRIPTION OF THE INVENTION One or more objects of the present invention are accomplished by the provision of a smoking composition comprising an admixture of combustible filler selected from natural tobacco, reconstituted tobacco and tobacco substitutes, and between about n.000]-5 weight percent, based on the total weight of filler, of a novel flavorant-release additive corresponding to the formula:

N

R R 1 1 2 R -C-C-R N 1 i 1 R P 0oo0 o 0 0.000 0 00 0 0 00 0 00 0 0o a o o0 o oo< ac a 0 a t *d t 1 where R is hydrogen or a C-C alkyl group; R 2 is hydrogen or a C -C alky] group; and R is a

C

3

-C

1 2 aromatic substituent; with the proviso that at least two RP groups are C -C alkyl groups.

1 8 15 Illustrative of the R substituent are hydrogen, methyl, ethyl, propyl, butyl, isobutyl and 2-butyl radicals.

Illustrative of the R substituent are R type of alkyl groups, and additionally can be selected 20 from higher alkyl radicals such as penty- 2-pentyl, hexyl, 2-hexyl, heptyl, octyl, isooctyl, and the like.

Il3ustrative of the R 2 substituents are substituted and unsubstituted aromatic structures such as phenyl, methoxyphenyl, tolyl, xylyl, naphthyl, and the like, and heteroaromatic structures (C C (C C

C

C

I

0 i.

j 1 I; monovalent radicals.

The preferred R2 substituents are substituted and unsubstituted phenyl, pyridyl and pyrazyl monovalent radicals.

In another embodiment this invention provides a novel pyr.azine composition corresponding to the formula: N R R R R 1 O i N 1 '1 R R

R

where R is hydrogen or a C 1

-C

4 alkyl group; and 1 Co R is hydrogen or a CI-C 8 alkyl group; with the 0 .001 8 proviso that at least two R 1 groups are C -C 8 000o alkyl radicals.

00015 When a present invention smoking composition is subjected to normal smoking conditions, the low o o0 o0 a volatility hetecoaromatic additive pyrolyzes into o o volatile components which enhance the flavor and aroma of low delivery cigarette smoke: 0 a 4 o o 0 00*.

',i;I -7- R R O R CRCOP N R P

N

R~ 0~~ R -C c-P N 1 11 p R The present invention heteroaromatic flavorant-release additives are stable and odorless compounds at ambient temperature. in addition, the additives decompose at a relatively low pyrolysis temperature 150 0 -300 0 C) to release a high yield of desirable flavor-enhancina heteroaromatic and carbonyl components in mainstream smoke.

0 0 0 00 00 A 0000 0 000 0 00 0 0 0 8 Preparation Of Heteroaromatic Compounds A general procedure for the preparation of present invention heteroaromalic flavorant-release Compounds involves the reaction of a selected alkylpyrazine anion with a carbonyl derivative in a solvent medium:

N

RP 0 P N) C-M C-P NI) 1 R P

N

Pc-M N 1 1 11

RP

-;P

31

N

R R~ 1 014 P 'NC C-P N I I1 I.

PRR

where M is a metal a'tom such as ithium, and R, and P 2 are as previously definedq.

An alternative procedure is preferred for the synthesis of a compound such as (P,S)-2-(l,1-dimethvl-2-hydroxv-2-phenylethyl)pyrazine in which steric hindrance by substituents is a factor: C t 0 .lj C C C C C k. C V O 0 2 t 9

N

CH OH i 3

C

3 [0)

II

N

N

CH 3-M

N

C CH N 3 0000 00 0 0 0000 00 a 00 0 0 00 a 01

N

N

j Preparation Of Smoking Compositions In a further embodiment this invention provides a methcJ of preparing a smoking composition which is adapted to impart flavor and aroma to mainstream and sidestream smoke under smoking conditions, which method comprises incorporating into natural tobacco, reconstituted tobacco or tobacco substitute between about 0.0001-5 weight percent, based on composition weight, of a flavorant-release additive corresponding to the formula:

N

R R 1

O

1N i 1 2 C P o 2 2 where R is hydrogen or a C-C 8 alkyl group; is hydrogen or a C 1 -Cg alkyl group; and R is a oo0 C 3-C12 aromatic substituent; with the proviso that 3 1 S°o15 at least two R groups are C -C alkyl radicals.

0 000 1 8 "o The invention flavorant-release additive can oo o be incorporated into the tobacco or tobacco substitute So a in accordance with methods known and used in the art.

Preferably the flavorant-release additive is dissolved So 0 0 20 in a solvent such as alcohol or aqueous alcohol and a on then sprayed or injected into the tobacco and/or 0 00 tobacco substitute matrix. Such method ensures an o "0 s even distribution of the flavorant additive throughout oo a the filler, and thereby facilitates the production of a more uniform smoking composition. Alternatively, 00 00 Do 0 0 0 0 0 0 1 o I::i i' 1t Y1 :i I _i -*1 _Ir *IYI 11 the flavorant may be incorporated as part of a concentrated tobacco extract which is applied to a fibrous tobacco web as in the manufacture of reconstituted tobacco. Another suitable procedure is to incorporate the flavorant in tobacco and/or tobacco substitute filler in a concentration between about 0.5-5 weight percent, based on the weight of filler, and then subsequently to blend the treated filler with filler which does not contain flavorant additive.

The term "tobacco substitute" is meant to include non-tobacco smokinq filler materials such as are disclosed in United States patents 3,703,177; 3,796,222; 4,019,521; 4,079,742; and references cited therein; incorporated herein by reference.

U.S. 3,703,177 describes a process for preparing a non-tobacco smoking product from sugar beet pulp, which process involves the acid hydrolysis of the beet pulp to release beet pectins, and at least oooo °oooo an alkaline earth treatment thereafter to cause 000 0ooo 20 crosslinking of the pectins and the formation of a 0°o bindina agent for the exhausted beet matrix.

0 000 000 o U.S. 3,796,222 describes a smokinq product o oo derived from coffee bean hulls. The hulls are treated 0 0 o oo with reagents that attack the alkaline earth metal crosslinks causino the release of the coffee pectins.

o o The pectins act as a binding agent and tooether with o oo the treated hulls may be handled and used similarly to 0 0 0 o o0 a tobacco product.

o000 o oo 0 0 0 O oo 00 0© 0 0 0 0 0 0 0 o o 0 00 o 00 o o LI_ L_ a r avoraniL- eitase au i L -v 1, UUIP Jl j ing, d L iT n compound according to any of claims 1 to 6 in an r'-tit t between 0.0001 and 5 weight percent, based on the total 2 1 12 U.S. 4,019,521 discloses a process for forming a smoking material which involves heating a cellulosic or carbohydrate material at a temperature of 150 0 -750 0 C in an inert atmosphere for a period of time sufficient to effect a weight loss of at least percent but not more than 90 percent.

U.S. 4,079,742 discloses a process for the manufacture of a synthetic smoking product from a cellulosic material, which process involves a pyrolysis step and a basic extraction step to yield a resultant matrix which has a tobacco-like brown color and has improved smoking characteristics.

The following Examples are further illustrative of the present invention. The specific ingredients and processing parameters are presented as being typical, and various modifications can be derived in view of the foregoing disclosure within the 000 scope of the invention.

0000 0000 0 t) Oa oo fo t 0 0 0 0 a t o 4e J~ i Li YI EXAMPLE I Preparation Of (R,S)-2-(2-Hydroxy-2-phenylethyl)-3-methylpyrazine

CH

3

OH

N 2 A solution of diisopropylamine (22.2 g, 0.22 mole) in ether (500 ml) is stirred under nitrogen atmosphere and treated with n-BuLi (0.20 mole) in hexane (119 ml) at -75 0 C. The resulting solution is warmed to VlC and a solution of 2,3-dimethylpyrazine (21.6 g, 0.20 mole) in ether (30 ml) is added slowly and the reaction mixture is stirred at 0 0 C for minutes.

5 A solution of benzaldehyde (21.2 g, S 0.20 mole) in ether (30 ml) is added and stirring at 15 0C is continued for an additional 30 minutes. Water is added to the reaction medium, then the organic layer is separated, washed with water, and dried over N a 2SO4 Evaporation of the solvent under reduced pressure provides an orance colored oil which is distilled bulb-to-bulb [155 0 -165 C (oven), 0.02 mm Hg) to give 22.2 q of a light yellow colored oil which crystallizes on standing. Recrystallization of the The following statement is a full description of this invention, including the best method of performing it known to me:-* Note: The description is to be typed in double spacing, -,ha type face, in an area not exceeding 250 mm in depth anid 160 mm in width, on tough white paper of good quality and it is to be insertedinside this form.

IL-

L I .14 crude product from ether yi;elds 13.84 a of product: mp 85 0 -86 0 C; 1H MMP (CDCl 3 2.47 Cs, 3H), 3.14 Cm, 2H), 4.83 Cd, 2H, J =2.9 HZ), 5.30 1H), 7.27-7.45 (in, 5H), 8.35 2P, J =2.7 HZ).

Anal. Calc. for C 13H 14N 20- C,72.87; fi,E.59; N,13.08 Found: C,73.19; H,6.88; m,13.09 0000 0 a 0 a06 41 000 0 0 44 0 4 4 (4 C 4 44.

0 EXAMPLE II Preparation Of 2Hydroxy-2-phenyJlethyl)-3-ethylpyrazile

N

C 2 H 5

OH

N CH 2 -C 1 A reaction of 2-ethyl-3--methylpyrazine (12.2 a, 0.01 mole) with benzaldehyde (10.6 9, 0.1 mole) is conducted in accordance with the procedure of Example I. Workup followed by bulb-to--bulb distillation (1550C oven/0.02 mm Hg) provides 18.2 g of a light yellow colored oil. This material crystallizes on trituration with hexane, 00 00 giving 17.80 g of desired product, 0 0 0 mp 52 0 53C V. An analytical sample is obtained by 4 a 15 recrystallization from hexane: Imp 53 0 -54'C; 1 H NMP.

Sa t (coD 3 1) 6 1.25 Ct, 3H, 3 7.4 Hz), 2.77 Cq, 2H, J= 7.4 Hz), 3.16 Cd, 2H, 3 6.2 Hz), 5.01 1H, 3 2.5 Hz), 5.28 Cm, IH), 7.27-7.46 Cm, 08.33 Cd, 1H, J 2.8 Hz), 8.40 111, J 2.8 Hz).

Anal. Calc. for C 1

H

6 N 0: C,73.65; H,7.06; N,12.27 Found: C,73.73, H,7.01; N,12.31

CC

C C C 16 EXAMPLE III Preparation Of C.8,)-2-(2-Hydroxy-2-phenylethyl)--3-isopropylpyrazine

CH

N 13 CH-CH 3O_ C, ICH CH A reaction of 2-isopropyl-3-methylpyrazine (0.62 q, 4.56 mmoles) with henzaldehyde (0.48 9, 4.56 mmoles) is conducted in accordance with the procedure of Example I. Workup followed by bulb-to-bulb distillation f100 0 -135 0 c (oven), 0.0) mm H91 provides 800 mg of a yellow-orange colored usin 1991 'cl 3/EtO toqive 386 ofa 0. cloressoil product which crystallizes be]low room *00 temperature: H NMP (CDC 3 6 1.20, 1.21, 1.24, 0 15 1.26 two doublets, 6, diastereotopic isopropyl methyl signals), 3.15-3.27 Cm, 3H), 5.02 Cd, 1H, J =2.6 Hz), .5.3 (in, 1H), 7.28-7.50 5H), 8.35 lH, J 2.4 Hz), 8.47 1H, 3 2.4 HZ).

An I Anal Calc. for C 15

H

1 NC0: C,74.35; H,7.49, N,11.56 Pound: C,74.16; H,7.35; N,11.33 as C C C Ing 0 00 0 17 EXAMPLE IV Preparation of 2-Mydroxy-2-phenylethyl )-3-isobutylpyrazine

CH

1 3

N

N

A reaction of 2-isobutyl-3-methylpyrazine qi, 20 mmoles) with benzaldehyde (2.12 g, mmoles) is conducted in accordance with the procedure of Example I. Standard workup is followed by bulb-to-bulb distillation [153 0 C (oven), 10 0.005 mm H91. The resultinq oil crystallizes on trituration with hexane to yield 2.5 qi of the desired product; mp 52 0 -53 0 c; 1 H NMM (CDC 3 6 0.92 3M, J 6.7 Hz), 2.0-2.2 1H), 2.62-2.64 Cm, 2H), 3.17 (in, 2R), 5.24-5.28 Cm, 1H), 7.25-7.45 Cm, 5M), 8.34 1P, J 2.5 Hz), 8.43 1H, J 2 .5 Hz) Anal. Calc. for C 16

H

20

N

2 0: C,74.96, H,7.86; N,10.93 Found: (,75.20l; H,7.73; N,10.87 0 0' Sc 0 4 C C C C C C C C C

AC

f 18 EXAMPLE V Preparation Of N CH3 CCH3 rectonof2tet.buyl3mehypya3n reida fraction usno slc 2-et ebtl.-and 85:15 zin hxnsaeneifolwdby 4* 4 15t l a i n 1 0 C ve .1 m H and (CDC 3) 6 1 44 s, H),3.2 (d I j 16.0, 4, 9 5 Hz .50 dd, 1H, 6.0, 2.2 5.23 t (hr d, 1H, J 9.0 Hz), 5.78 1H), 7.30-7.52 (in, 5H) 0.38 1H, J 2.2 Hz), 8.147 1H, J 2.2 Hz).

44 Anal. Calc. for C 1 6

H

2 0 N 2 0 C'74.96; H,7.86; N,10.93 444, ound: C,74.83, H,7.98; N,10.88 19 EXAMPLE VI Preparation Of (IRS, 2SR)-2-(l-Methyl-2-hydroxy-2phenylethyl)pyrazine and (IRS, 2PS)-2-(1--Methyl-2--hydroxy-2pheny-lethyl)pyrazine (B)

-N

CH OH 3HC A reaction of ethylpyrazine (10.8 g, 0.1 mole) with benzaldehyde (10.6 g, 0.1 mole) is conducted in accordance with the procedure of Example I. Workup afforded a diastereoisomeric mixture of (Rf 0.25 on silica 4:1 hexane/acetone) and (RP 0.18).

The mixture is separated by centrifugal chromatography usina 100:15 hexanes/acetone to yield pure diastereoisomers.

mp 79'-80 0 C; H NMR (CDCI 6 1.30 3H, 3 7.0 Hz), 3.23 (dq, 1H, 3 7.0, 3.5 Hz), 4.19 1H, J 2.0 Hiz), 5.16 (br t, lH), 7.38 (br s, 8.42 (in, 3H).

.4* .4.4 9 .4, 0 9.420 40 004.4 0 .4 p4, 9 0* 90 .4 .4 9 4, 47 .4.4 .4 .4 .4 .4 .4 .4.4 Anal. Calic. for C 13H 14N 2 0 Found: C,72.87; H,6.59, N,13.08 C,72.82; H,6.66; N,13.05 '4 20 mp 58 0 -59 0 H NMR (CDC 3 6 1.28 3H J 7 .0 HZ), 3. 35 pentet 1H., J 7 7.0 HZ) 3.70 1H, i 5.8 HZ), 5.05 (dd, 1H, J 7.0, 5.8 Hz), 7.40 (br s, 5H), 8.50-8.68 (mn, 3H).

Anal. Calc. for c 1 H 14N 20: C,72.87, H,6.59; N,13.08 Found: C,72.95, H,6.50; N ,13.13 0 0 0444 4440 0*00 *0 040 *0 4 o 0 0 04 *0 0 4 4 to oslo 4 t 4 00* -21- EXAMPLE VII Preparation Of (fl,)-2-(2-Hydroxy-2-phenylpropyl)pyrin

N

OH

N 2 F -H 3 A reaction of 2-methylpyrazine (4.7 g, 0.05 mole) with acetophenone (6.6 g, 0.055 mole) is conducted in accordance with the procedure of Example I. workup followed by bulb-to-bulb distillation and centrifugal chromatography using 85:15 hexanes/acetone on silica gel yields 454 mg 0 of the desired product: mp 53 0 -54 0

C

(from hexane); H WIP (CoD 3 1) 6 1.61 3H), 0,3.35 2P9), 5.35 (hr s, 1H9, 7.18-7.63 *0 8.38-8.55 (in, 3H).

a 10~:5 Anal. Calc. for C 13H 14N 20: C,72.87; H9,6.59; N,13.08 FounlI: C173.03; H,6.58; N,13.04 4 C C, Cc t C 22 EXAMPLE VIII Preparation of (B,.S)-2-(l,l-Dimethyl-2-hydroxy-2-phenylethyl)pyrazine

N

CH OH

CN)C-CH

3 A reaction of isopropylpyrazine (439 mg, 3.6 mmoies) with benzaldehyde (456 mg, 4.33 mmoles) is conducted by means of the Example I procedure with the stirrino time extended to 1.5 hours. Workup is followed by bulb-to-bulb distillation [105 0 -160 0

C

Coven), 0.01 mm Hg] to give a semi-solid. The resultant material is purified directly by centrifugal chromatography on silica qel usin' 100:14:3.6 hexanes/acetone/EtOH to yield 177 mQ of 1 product: mp 901-911c; H NMP (CDCl 6 1.39 -3 3H), 1.40 3H), 4.50 Cd, IH, J 4.5 Hz), 4.95 lH, J 4.5 Hz), 7.107.2CH)72472 Cm, 3H), 8.51-8.58 (in, 3H).

I A I Anal. Calc. for C H NO0: C,73.65; H,7.06; 14,12.27 a t *a 14 16 2 C,73.27; H,6.96; N,12.13 A reaction of tetramethylpyrazine with 3-acetylpyridine yields (R,S)-2-[2-hydroxy-2a a C3-pyridyl)propyl]-3,5,6-trimetlhylpyrazine.

23 EXAMPLE IX Preparation Of A Mixture Of (lRS,2RS)-2-(1-methyl-2-hydroxy-2phenylpropyl)pyrazine and (1RS,2SR)-2-(l-methyl-2-hydroxy-2phenyipropyl)pyrazine

N

CH OH S CH---3 CH 3 A reaction of ethylpyrazine (5.40 q, 0.05 mole) with acetophenone (6.0 g, 0.05 mole) is conducted in accordance with the previously described procedure. Workup afforded an oil which was crystallized from cyclohexane to yield 3.7 g of the aoo 1 n desired product: m.p. 88 0 -108 0 C. H NMR confirms the above structure and indicates about 1:1 mixture of 0000 :o 15 the two diastereoisomers.

6 Anal. Calc. for C14 H 16N 20 C,73.65; H,7.06; N,12.27 Found: C,73.60; H,7.20; N,12.19 A reaction of tetraethylpyrazine with acetophenone yields a 1-position diastereoisomeric mixture of 2-(1-methyl-2-hydroxy-2-phenylpropyl)-3,5,6triethylpyrazines.

4: 4,4 -24 EXAMPLE X Preparation Of

CN

I II 3 *3 A stirred and cooled (0 0 c) solution of 1, l-dimethyl--2-hydroxy-2-phenylethyl )pyrazine (1 g, 4.38 mmoles) in acetone (150 ml) is treated with an aqueous solution of CrO -H so 4 (1.39 ml, 3.72 mmoles). The solution is stirred for 10 minutes, diluted with water (500 ml), allowed to stand for 1 hour and then basified Ctla 2

CO

3 The solution is extracted with CH Cl 2 and the CH C1 2 extract is dried CNa so and concentrated to provide 1.2 g of a turbid oil. Purification by centrifugal chromatography on silica gel and elutina with 100:15:3 hexanes/acetone/EtOH yields 710 ma (71%) of l-(l-phenyl-2-methyl-2-pyrazinyl)propanone: mp 67 0 -68 0 C; 1 H NMP (CDCl 6 1.73 6H), 3 7.23-7.48 Cm, 5H), 8.46-8.59 3H).A Anal. Calc. for C H N 0: C,74.31, H,6.24, N,l2.3 8 14 14 2 Found: C 74 22 H,6.10, N,12.23 -I r-Li I i I I A solution of the prepared ketone (390 mg, 1.73 mmoles) in ether (100 ml) is stirred at -70 0 C and treated with 2.23 mmoles) of MeLi in ether (2.23 ml).

The reaction is quenched with MeOH after being stirred for 2 hours at -65 0 C. The resultant mixture is concentrated and the residue is taken up in CH2Cl2, dried (Na2 SO and filtered.

Purification by centrifugal chromatography on silica gel with 95:4:1 hexanes/acetone/EtOH yields 221 mg 1 of the desired product: mp 99 0 -100 0 C; H NMR (CDC1 3 6 1.37 3H), 1.44 3H), 1.47 3H), 5.68 1H), 7.21-7.34 5H), 8.48-8.54 3H).

Anal. Calc. for C 15

H

18

N

2 0: C,74.35; H,7.49; N,11.56 Found: C,74.23; H,7.61; N,11.48 1 l

F

1 26 EXAMPLE XI Preparation Of (R,S)-2-(l,l-Dimethyl-2-hydroxy-2-phenylethyl)-3isopropylpyrazine .N CH CH-CH 3 CH 01H j3

C-CH

A solution of lithium diisopropylamide in ether is prepared as described in Example I from diisopropylamine (676 mq, 6.7 mmoles) and n-BuLi (6.6 mmoles) in 2.67 ml of hexane at -751C. The resultino solution is warmed to O'C and a solution of 2,3-diisopropylpyrazine (1.0 q, 6.1 mmoles) in ether (2 ml) is added slowly and the reaction mixture is stirred under reflux for 2 hours. The mixture is then treated with benzeldehyde (0.78 9, 7.32 mmoles) as 15 described in Example I.

0 0 Workup followed by purification using centrifugal chromatography and recrystallization from hexane affords 10.6 mq of I -limethyl-2-hydroxy-2-phenylethyl isopropylpyrazine: M.P. 128 0 -128.5 0 C; 1H NMR (cDCl' 3 6 1.25 3H, J 7 HZ) 1. 27 (s 3H), 1.30 3H, J =7.0 Hz), 1.48 3H), 3.59 (heptet, 1H J 7 .0 Hz) 4 .96 br d, lH 3 3 .3 Hz C-HOH) 5.28 (br d, 1H, J 3.3 Hz, CHOH), 7.2-7.4 :025 8.31 lH, J, 3 25H)848dl,3 2.5 Hz) Anal. Calc. for C 17H 22N 20: C,75.52; H,8.20; N,10.36 Found: C,75.31; H,8.23; N,l0.30 1' 27 EXAMPLE XII This Example demonstrates first order rate constants for the pyrolysis of present invention pyrazine compounds in comparison with prior art pyrazine compounds.

The pyrolysis reactions are conducted in diglyme-dl4 (Merck Sharp Dohme, Canada, Ltd.) that is dried over a molecular sieve. A 0.4 M solution of each of the pyrazines (0.5 ml) is placed in a thick-walled NMR tube, and the tubes are sealed.

Kinetic runs are performed in a constant-temperature oil bath preheated to the desired temperature (170 0.8 C).

The progress of each pyrolysis is followed by NMP spectroscopy employing a method described in J. Org. Chem. 45, 999 Percentage compositions are calculated from integration of peaks of both 4,4: reactants and products mainly in the aromatic Sregions. In each case the reaction proceeds smoothly with only the parent pyrazine and carbonyl product detected in the reaction mixture. First order rate constants are calculated and the comparative data are summarized in the Table.

The comparative data demonstrate that the 25 heteroaromatic compounds of Examples VIII-X in accordance with the present invention pyrolyze at a 4 significantly higher rate than known heteroaromatic compounds of related structure.

f ;I I i 1~ 1 6r 28 When a present invention heteroaromatic compound is utilized as a smoking composition flavorant-release additive, the fast rate of pyrolysis delivers a high yield of volatile pyrazine and carbonyl components which are effective for enhancement of the flavor and aroma of generated smoke.

4000 0 00000 04 o 0to 0006 0 O 000 00 0 0 00 00 0 00 0 0 0 0 4 4, I o 0 4 o '4 ao o t 0 0 00 4 1 0 0 0 4' 04 ij

F

:t i t i a i 29

TABLF

N

N

A

N. 1 R2 I CH

C

N 3 i4 R P- 1 0'~00 0 ~00 0000 4 0000 4 boo 0~ 0 4.0 00 4.

00 0 0 40 0 04 00 O 0 0 0 44.

0 00 0 0 4 4. 40 0004.

0 00 00 0 Example Compound P 1

H

TH

C

3 ICH 2 CH 3 IICH(CH 3 2 IV CH 2 CH(H 3 )2 V C(CH 3 3 VI H p 2

H

H

H

H

H

H

CP 3

H

H

CH3 H((P

H

3 mixture of CH 3 p 3

P

4

HH

HH

HH

HH

H H

HH

c P 3

H

CO H CH3 diastereoisomers CH 3 OC1

H

H

1 .81 9 .36 8 .69 9.06 13 .13 5 4 4 .61 8 .91 53 .77 18 .57 4 26 5 n sec- X VT T

VTIII

Tx 00 0 0 0 0 90 0 0 0~ Ory. Chem., 45, 999(1980).

Claims (11)

1. A pyrazine compound corresponding to the formula: N R R. X OH R R where R is hydrogen or a C -C 4 alkyl group; and R 1 is i-,ydrogen or a C 1 -C 8 alkyl group; with the proviso that at least two Rlgroups are C 1 -C 8 alkyl radicals.

2. 2-(l,1-Dimethyl-2-hydroxy-2--phenylethyl)-pyrazine.

3. 2-(l-Methyl-2-hydroxy-2-phenylpropyl )-pyrazine.

4. 2-(1,1-dimethyl-2-hydroxy-2-phenylpropyl) Doc* pyrazine. 99 2-(l,1-Dimethyl-2-hydroxy-2-phenylethyl)-3- 0 isopropylpyrazine.

6. 2-(2-llydroxy-2-phenylethyl) -3-tertiary- 9 butylpyrazine.

7. A smoking composition comprising an admixture of combustible f iller selected f rom natural tobacco, reconstituted tobacco and. tobacco substitutes and (2) a flavorant-release additive, comprising a pyrazine compound according to any of claims 1 to 6 in an amount between 0. 0001 and 5 weight percent, based on the total 9: weight of filler. -31-

8. A smoking composition comprising an admixture of combustible filler selected from natural tobacco, reconstituted tobacco and tobacco substitutes, and (2) a flavorant-release additive corresponding to the formula: R X R 1 S I R 2 R C-C-R N I I I I PR where R is hydrogen or a C -C 4 alky] group; R 1 is hydrogen or a C 1 -C 8 alkyl group; and R 2 is a C3-C12 aromatic substituent; with the proviso that at least 1 two R groups are CI-C 8 alkyl radicals; which is present in an amount between 0.0001 and 5 weight percent based on the total weight of filler. o 9. A smoking composition in accordance with claim 8 o,06 2 oso, wherein R is a phenyl radical. Oo c oo 10. A smoking composition in accordance with claim 8 0 0 2 o wherein R is a naphthyl radical. o e U

11. A smoking composition in accordance with claim 8 wherein R is a pyridyl radical. 0i CU o 12. A smoking composition in accordance with claim 8 wherein R2 is a pyrazyl radical.

13. A smoking composition in accordance with claim 8 wherein R 2 is a thiazyl radical. 0 o0 14. A smoking composition in accordance with claim Ylr i 32 -32- 8 wherein R 2 is a furyl radical. A smoking composition in accordance with claim 8, wherein R is a thienyl radical.

16. A smoking composition, substantially as herein described with reference to any one of the Examples II to VI or VIII to X.

17. A method of preparing a smoking composition which comprises incorporating into natural tobacco, reconstituted tobacco or tobacco substitute between 0.0001 and 5 weight percent, based on composition weight, of a flavor release additive as defined in either claim 7 or claim 8. DATED this 18th day of November 1991. 1o So oPHILIP MORRIS PRODUCTS INC. S o By their Patent Attorneys: CALLINAN LAWRIE 4 I a a. a a